2017年02月, 日本学術振興会, 海外特別研究員　　　　　　　　　　　　　　　

2015年04月, アレキサンダー・フォン・フンボルト財団, フンボルト研究奨学金　　　　　　　　　　　　　　　

2013年09月, 日本生化学学会, 第86回日本生化学学会 鈴木紘一メモリアル賞　　　　　　　　　　　　　　　

2013年06月, トランスポーター研究会, 第8回トランスポーター研究会年会 優秀ポスター賞　　　　　　　　　　　　　　　

2012年01月, 国際亜鉛生物学会, 第6回国際亜鉛生物学会学術集会 トラベルアワード　　　　　　　　　　　　　　　

2011年06月, トランスポーター研究会, 第6回トランスポーター研究会年会 優秀ポスター賞　　　　　　　　　　　　　　　

2007年04月, 理化学研究所, ジュニアリサーチアソシエイト（JRA）　　　　　　　　　　　　　　　

2005年10月, 国立医療学会, 第38回塩田賞　　　　　　　　　　　　　　　

GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis.
Ryutaro Furukawa, Masaki Kuwatani, Jing-Jing Jiang, Yuki Tanaka, Rie Hasebe, Kaoru Murakami, Kumiko Tanaka, Noriyuki Hirata, Izuru Ohki, Ikuko Takahashi, Takeshi Yamasaki, Yuta Shinohara, Shunichiro Nozawa, Shintaro Hojyo, Shimpei I Kubota, Shigeru Hashimoto, Satoshi Hirano, Naoya Sakamoto, Masaaki Murakami
Scientific reports, 14, 1, 12224, 12224, 2024年05月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation
Seiichiro Naito, Hiroki Tanaka, Jing-Jing Jiang, Masato Tarumi, Ari Hashimoto, Yuki Tanaka, Kaoru Murakami, Shimpei I. Kubota, Shintaro Hojyo, Shigeru Hashimoto, Masaaki Murakami
Biochemical and Biophysical Research Communications, 703, 149666, 149666, Elsevier BV, 2024年04月
研究論文（学術雑誌）

High-precision rapid testing of omicron SARS-CoV-2 variants in clinical samples using AI-nanopore.
Kaoru Murakami, Shimpei I Kubota, Kumiko Tanaka, Hiroki Tanaka, Keiichiroh Akabane, Rigel Suzuki, Yuta Shinohara, Hiroyasu Takei, Shigeru Hashimoto, Yuki Tanaka, Shintaro Hojyo, Osamu Sakamoto, Norihiko Naono, Takayui Takaai, Kazuki Sato, Yuichi Kojima, Toshiyuki Harada, Takeshi Hattori, Satoshi Fuke, Isao Yokota, Satoshi Konno, Takashi Washio, Takasuke Fukuhara, Takanori Teshima, Masateru Taniguchi, Masaaki Murakami
Lab on a chip, 23, 22, 4909, 4918, 2023年11月07日, ［国際誌］
英語, 研究論文（学術雑誌）, A digital platform that can rapidly and accurately diagnose pathogenic viral variants, including SARS-CoV-2, will minimize pandemics, public anxiety, and economic losses. We recently reported an artificial intelligence (AI)-nanopore platform that enables testing for Wuhan SARS-CoV-2 with high sensitivity and specificity within five minutes. However, which parts of the virus are recognized by the platform are unknown. Similarly, whether the platform can detect SARS-CoV-2 variants or the presence of the virus in clinical samples needs further study. Here, we demonstrated the platform can distinguish SARS-CoV-2 variants. Further, it identified mutated Wuhan SARS-CoV-2 expressing spike proteins of the delta and omicron variants, indicating it discriminates spike proteins. Finally, we used the platform to identify omicron variants with a sensitivity and specificity of 100% and 94%, respectively, in saliva specimens from COVID-19 patients. Thus, our results demonstrate the AI-nanopore platform is an effective diagnostic tool for SARS-CoV-2 variants.

GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation.
Shiina Matsuyama, Reiji Yamamoto, Kaoru Murakami, Nobuhiko Takahashi, Rieko Nishi, Asuka Ishii, Junko Nio-Kobayashi, Nobuya Abe, Kumiko Tanaka, Jing-Jing Jiang, Tadafumi Kawamoto, Toshihiko Iwanaga, Yuta Shinohara, Takeshi Yamasaki, Izuru Ohki, Shintaro Hojyo, Rie Hasebe, Shimpei I Kubota, Noriyuki Hirata, Daisuke Kamimura, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
Journal of immunology (Baltimore, Md. : 1950), 211, 1, 34, 42, 2023年07月01日, ［国際誌］
英語, 研究論文（学術雑誌）, We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common β chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS.

Computer model of IL-6-dependent rheumatoid arthritis in F759 mice
Reiji Yamamoto, Satoshi Yamada, Toru Atsumi, Kaoru Murakami, Ari Hashimoto, Seiichiro Naito, Yuki Tanaka, Izuru Ohki, Yuta Shinohara, Norimasa Iwasaki, Akihiko Yoshimura, Jing-Jing Jiang, Daisuke Kamimura, Shintaro Hojyo, Shimpei I Kubota, Shigeru Hashimoto, Masaaki Murakami
International Immunology, Oxford University Press (OUP), 2023年05月25日
研究論文（学術雑誌）, Abstract

The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases.

In situ Microinflammation Detection Using Gold Nanoclusters and a Tissue-clearing Method.
Fayrouz Naim, Rie Hasebe, Shintaro Hojyo, Yukatsu Shichibu, Asuka Ishii, Yuki Tanaka, Kazuki Tainaka, Shimpei I Kubota, Katsuaki Konishi, Masaaki Murakami
Bio-protocol, 13, 7, e4644, 2023年04月05日, ［国際誌］
英語, 研究論文（学術雑誌）, Microinflammation enhances the permeability of specific blood vessel sites through an elevation of local inflammatory mediators, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. By a two-dimensional immunohistochemistry analysis of tissue sections from mice with experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), we previously showed that pathogenic immune cells, including CD4+ T cells, specifically accumulate and cause microinflammation at the dorsal vessels of the fifth lumbar cord (L5), resulting in the onset of disease. However, usual pathological analyses by using immunohistochemistry on sections are not effective at identifying the microinflammation sites in organs. Here, we developed a new three-dimensional visualization method of microinflammation using luminescent gold nanoclusters (AuNCs) and the clear, unobstructed brain/body imaging cocktails and computational analysis (CUBIC) tissue-clearing method. Our protocol is based on the detection of leaked AuNCs from the blood vessels due to an enhanced vascular permeability caused by the microinflammation. When we injected ultrasmall coordinated Au13 nanoclusters intravenously (i.v.) to EAE mice, and then subjected the spinal cords to tissue clearing, we detected Au signals leaked from the blood vessels at L5 by light sheet microscopy, which enabled the visualization of complex tissue structures at the whole organ level, consistent with our previous report that microinflammation occurs specifically at this site. Our method will be useful to specify and track the stepwise development of microinflammation in whole organs that is triggered by the recruitment of pathogenic immune cells at specific blood vessels in various inflammatory diseases.

Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.
Takeshi Yamasaki, Noriyuki Nagata, Toru Atsumi, Rie Hasebe, Yuki Tanaka, Izuru Ohki, Shimpei Kubota, Yuta Shinohara, Yong Bin Teoh, Nozomu Yokoyama, Noboru Sasaki, Kensuke Nakamura, Hiroshi Ohta, Takehiko Katsurada, Yoshihiro Matsuno, Shintaro Hojyo, Shigeru Hashimoto, Mitsuyoshi Takiguchi, Masaaki Murakami
International immunology, 35, 7, 313, 326, 2023年03月18日, ［国際誌］
英語, 研究論文（学術雑誌）, Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD), and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2, and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G>T and c.478A>T, and found that ICRPs with the T/T SNP risk-alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk-alleles but no differences in serum. Moreover, we show that MMP9, which is a NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were colocalized with epithelial cells expressing MMP9 in normal colons with the risk-alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also colocalized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.

Dupuytren's contracture-associated SNPs increase SFRP4 expression in nonimmune cells including fibroblasts to enhance inflammation development.
Hiroaki Kida, Jing-Jing Jiang, Yuichiro Matsui, Ikuko Takahashi, Rie Hasebe, Daisuke Kawamura, Takeshi Endo, Hiroki Shibayama, Makoto Kondoh, Yasuhiko Nishio, Kinya Nishida, Yoshihiro Matsuno, Tsukasa Oikawa, Shimpei Kubota, Shintaro Hojyo, Norimasa Iwasaki, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
International immunology, 35, 7, 303, 312, 2023年01月31日, ［国際誌］
英語, 研究論文（学術雑誌）, Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two SNPs associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors, and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

Sjögren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development.
Shuhei Shimoyama, Ikuma Nakagawa, Jing-Jing Jiang, Isao Matsumoto, John A Chiorini, Yoshinori Hasegawa, Osamu Ohara, Rie Hasebe, Mitsutoshi Ota, Mona Uchida, Daisuke Kamimura, Shintaro Hojyo, Yuki Tanaka, Tatsuya Atsumi, Masaaki Murakami
International immunology, 33, 8, 423, 434, 2021年07月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.

Biliary excretion of excess iron in mice requires hepatocyte iron import by Slc39a14.
Milankumar Prajapati, Heather L Conboy, Shintaro Hojyo, Toshiyuki Fukada, Bogdan Budnik, Thomas B Bartnikas
The Journal of biological chemistry, 297, 1, 100835, 100835, 2021年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Iron is essential for erythropoiesis and other biological processes, but is toxic in excess. Dietary absorption of iron is a highly regulated process and is a major determinant of body iron levels. Iron excretion, however, is considered a passive, unregulated process, and the underlying pathways are unknown. Here we investigated the role of metal transporters SLC39A14 and SLC30A10 in biliary iron excretion. While SLC39A14 imports manganese into the liver and other organs under physiological conditions, it imports iron under conditions of iron excess. SLC30A10 exports manganese from hepatocytes into the bile. We hypothesized that biliary excretion of excess iron would be impaired by SLC39A14 and SLC30A10 deficiency. We therefore analyzed biliary iron excretion in Slc39a14-and Slc30a10-deficient mice raised on iron-sufficient and -rich diets. Bile was collected surgically from the mice, then analyzed with nonheme iron assays, mass spectrometry, ELISAs, and an electrophoretic assay for iron-loaded ferritin. Our results support a model in which biliary excretion of excess iron requires iron import into hepatocytes by SLC39A14, followed by iron export into the bile predominantly as ferritin, with iron export occurring independently of SLC30A10. To our knowledge, this is the first report of a molecular determinant of mammalian iron excretion and can serve as basis for future investigations into mechanisms of iron excretion and relevance to iron homeostasis.

Characterization of in vitro models of SLC30A10 deficiency.
Milankumar Prajapati, Michael A Pettiglio, Heather L Conboy, Courtney J Mercadante, Shintaro Hojyo, Toshiyuki Fukada, Thomas B Bartnikas
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine, 34, 3, 573, 588, 2021年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Manganese (Mn), an essential metal, can be toxic at elevated levels. In 2012, the first inherited cause of Mn excess was reported in patients with mutations in SLC30A10, a Mn efflux transporter. To explore the function of SLC30A10 in vitro, the current study used CRISPR/Cas9 gene editing to develop a stable SLC30A10 mutant Hep3B hepatoma cell line and collagenase perfusion in live mice to isolate primary hepatocytes deficient in Slc30a10. We also compared phenotypes of primary vs. non-primary cell lines to determine if they both serve as reliable in vitro models for the known physiological roles of SLC30A10. Mutant SLC30A10 Hep3B cells had increased Mn levels and decreased viability when exposed to excess Mn. Transport studies indicated a reduction of 54Mn import and export in mutant cells. While impaired 54Mn export was hypothesized given the essential role for SLC30A10 in cellular Mn export, impaired 54Mn import was unexpected. Whole genome sequencing did not identify any additional mutations in known Mn transporters in the mutant Hep3B mutant cell line. We then evaluated 54Mn transport in primary hepatocytes cultures isolated from genetically altered mice with varying liver Mn levels. Based on results from these experiments, we suggest that the effects of SLC30A10 deficiency on Mn homeostasis can be interrogated in vitro but only in specific types of cell lines.

Gateway reflexes, neuronal circuits that regulate the gateways for autoreactive T cells in organs that have blood barriers.
Mona Uchida, Reiji Yamamoto, Shiina Matsuyama, Kaoru Murakami, Rie Hasebe, Shintaro Hojyo, Yuki Tanaka, Masaaki Murakami
International immunology, 2021年05月12日, ［査読有り］, ［招待有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Gateway reflexes are neural circuits that maintain homeostasis of the immune system. They form gateways for autoreactive T cells to infiltrate the central nervous system in a noradrenaline-dependent manner despite the blood-brain barrier. This mechanism is critical not only for maintaining organ homeostasis but also for inflammatory disease development. Gateway reflexes can be regulated by environmental or artificial stimuli including electrical stimulation, suggesting that the infiltration of immune cells can be controlled by bioelectronic medicine. In this review, we describe the discovery of gateway reflexes and their future directions with special focus on bioelectronic medicine.

Gateway Reflex and Mechanotransduction.
Shiina Matsuyama, Yuki Tanaka, Rie Hasebe, Shintaro Hojyo, Masaaki Murakami
Frontiers in immunology, 12, 780451, 780451, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, The gateway reflex explains how autoreactive CD4+ T cells cause inflammation in tissues that have blood-barriers, such as the central nervous system and retina. It depends on neural activations in response to specific external stimuli, such as gravity, pain, stress, and light, which lead to the secretion of noradrenaline at specific vessels in the tissues. Noradrenaline activates NFkB at these vessels, followed by an increase of chemokine expression as well as a reduction of tight junction molecules to accumulate autoreactive CD4+ T cells, which breach blood-barriers. Transient receptor potential vanilloid 1 (TRPV1) molecules on sensory neurons are critical for the gateway reflex, indicating the importance of mechano-sensing. In this review, we overview the gateway reflex with a special interest in mechanosensory transduction (mechanotransduction).

Multiple developmental pathways lead to the generation of CD4 T cell memory.
Shintaro Hojyo, Damon Tumes, Akihiko Murata, Koji Tokoyoda
International immunology, 2020年08月07日, ［査読有り］, ［招待有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Long-term immunological memory mediated by CD4 T cells provides a rapid protection against previously encountered pathogens or antigens. However, it is still controversial how memory CD4 T cells are generated and maintained. Unclear definitions of T cell memory may be partially responsible for this controversy. It is becoming clear that diverse pathways are responsible for the differentiation and long-term persistence of memory T cells. We herein discuss the diversity of memory cell generation, describing a novel population of resting memory CD4 T cells and their precursors.

How COVID-19 induces cytokine storm with high mortality.
Shintaro Hojyo, Mona Uchida, Kumiko Tanaka, Rie Hasebe, Yuki Tanaka, Masaaki Murakami, Toshio Hirano
Inflammation and regeneration, 40, 37, 37, 2020年, ［査読有り］, ［招待有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.

Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow.
Christian Männe, Akiko Takaya, Yuzuru Yamasaki, Mathias Mursell, Shintaro Hojyo, Tsung-Yen Wu, Jana Sarkander, Mairi A McGrath, Rebecca Cornelis, Stefanie Hahne, Qingyu Cheng, Tadafumi Kawamoto, Falk Hiepe, Stefan H E Kaufmann, Tomoko Yamamoto, Andreas Radbruch, Koji Tokoyoda
Proceedings of the National Academy of Sciences of the United States of America, 116, 15, 7425, 7430, 2019年04月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella A SiiE-derived peptide with homology to laminin β1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin β1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.

Revisiting the old and learning the new of zinc in immunity.
Toshiyuki Fukada, Shintaro Hojyo, Takafumi Hara, Teruhisa Takagishi
Nature immunology, 20, 3, 248, 250, 2019年03月, ［査読有り］, ［招待有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Enhanced Cell Division Is Required for the Generation of Memory CD4 T Cells to Migrate Into Their Proper Location.
Jana Sarkander, Shintaro Hojyo, Mathias Mursell, Yuzuru Yamasaki, Tsung-Yen Wu, Damon J Tumes, Kosuke Miyauchi, Cam Loan Tran, Jinfang Zhu, Max Löhning, Andreas Hutloff, Mir-Farzin Mashreghi, Masato Kubo, Andreas Radbruch, Koji Tokoyoda
Frontiers in immunology, 10, 3113, 3113, 2019年, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, CD4 T cell memory is fundamental for long-lasting immunity and effective secondary responses following infection or vaccination. We have previously found that memory CD4 T cells specific for systemic antigens preferentially reside in the bone marrow (BM) and arise from splenic CD49b+T-bet+ CD4 T cells. However, how BM-homing memory precursors are generated during an immune reaction is unknown. We show here that BM memory precursors are generated via augmented rates of cell division throughout a primary immune response. Treatment with the cytostatic drug cyclophosphamide or blockade of the CD28/B7 co-stimulatory pathway at the beginning of the contraction phase abrogates the generation of BM memory precursors. We determine that, following a critical number of cell divisions, memory precursors downregulate CCR7 and upregulate IL-2Rβ, indicating that loss of CCR7 and gain of IL-2 signal are required for the migration of memory precursors toward the BM.

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle.
Gang Wang, Anup K Biswas, Wanchao Ma, Manoj Kandpal, Courtney Coker, Paul M Grandgenett, Michael A Hollingsworth, Rinku Jain, Kurenai Tanji, Sara Lόpez-Pintado, Alain Borczuk, Doreen Hebert, Supak Jenkitkasemwong, Shintaro Hojyo, Ramana V Davuluri, Mitchell D Knutson, Toshiyuki Fukada, Swarnali Acharyya
Nature medicine, 24, 6, 770, 781, 2018年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

Disruption of the mouse Slc39a14 gene encoding zinc transporter ZIP14 is associated with decreased bone mass, likely caused by enhanced bone resorption.
Sun Sasaki, Manami Tsukamoto, Masaki Saito, Shintaro Hojyo, Toshiyuki Fukada, Masamichi Takami, Tatsuya Furuichi
FEBS open bio, 8, 4, 655, 663, 2018年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Osteoclasts are bone-resorbing cells that play an essential role in maintaining bone homeostasis. Zinc (Zn) has been reported to inhibit osteoclast-mediated bone resorption, but the mechanism of this action has not been clarified. Zn homeostasis is tightly controlled by the coordinated actions of many Zn transporters. The Zn transporter ZIP14/Slc39a14 is involved in various physiological functions; hence, Zip14-knockout (KO) mice exhibit multiple phenotypes. In this study, we thoroughly investigated the bone phenotypes of Zip14-KO mice, demonstrating that the KO mice exhibited osteopenia in both trabecular and cortical bones. In Zip14-KO mice, bone resorption was increased, whereas the bone formation rate was unchanged. Zip14 mRNA was expressed in normal osteoclasts both in vivo and in vitro, but receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis was not impaired in bone marrow-derived macrophages prepared from Zip14-KO mice. These results suggest that ZIP14 regulates bone homeostasis by inhibiting bore resorption and that in Zip14-KO mice, bone resorption is increased due to the elimination of this inhibitory regulation. Further studies are necessary to conclude whether the enhancement of bone resorption in Zip14-KO mice is due to a cell-autonomous or a non-cell-autonomous osteoclast defect.

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice.
Supak Jenkitkasemwong, Adenike Akinyode, Elizabeth Paulus, Ralf Weiskirchen, Shintaro Hojyo, Toshiyuki Fukada, Genesys Giraldo, Jessica Schrier, Armin Garcia, Christopher Janus, Benoit Giasson, Mitchell D Knutson
Proceedings of the National Academy of Sciences of the United States of America, 115, 8, E1769-E1778, 2018年02月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of Slc39a14 knockout (Slc39a14-/-) mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that Slc39a14-/- mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, Slc39a14-/- mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using 54Mn reveal that Slc39a14-/- mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of Slc39a14-/- mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in Slc39a14-/- mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in Slc39a14-/- mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in Slc39a14-/- mice suggests that the motor impairments represent lasting effects of early-life Mn exposure.

The Role of the Slc39a Family of Zinc Transporters in Zinc Homeostasis in Skin.
Bum-Ho Bin, Shintaro Hojyo, Juyeon Seo, Takafumi Hara, Teruhisa Takagishi, Kenji Mishima, Toshiyuki Fukada
Nutrients, 10, 2, 2018年02月16日, ［査読有り］, ［招待有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The first manifestations that appear under zinc deficiency are skin defects such as dermatitis, alopecia, acne, eczema, dry, and scaling skin. Several genetic disorders including acrodermatitis enteropathica (also known as Danbolt-Closs syndrome) and Brandt's syndrome are highly related to zinc deficiency. However, the zinc-related molecular mechanisms underlying normal skin development and homeostasis, as well as the mechanism by which disturbed zinc homeostasis causes such skin disorders, are unknown. Recent genomic approaches have revealed the physiological importance of zinc transporters in skin formation and clarified their functional impairment in cutaneous pathogenesis. In this review, we provide an overview of the relationships between zinc deficiency and skin disorders, focusing on the roles of zinc transporters in the skin. We also discuss therapeutic outlooks and advantages of controlling zinc levels via zinc transporters to prevent cutaneous disorganization.

Dysregulated zinc homeostasis in rare skin disorders
Shintaro Hojyo, Bum Ho Bin, Toshiyuki Fukada
Expert Opinion on Orphan Drugs, 5, 11, 865, 873, 2017年11月02日, ［査読有り］, ［招待有り］, ［筆頭著者］
© 2017 Informa UK Limited, trading as Taylor & Francis Group. Introduction: Zinc (Zn) is an essential trace element required for normal skin homeostasis. Therefore, cutaneous changes are often observed in Zn-deficient patients. Acrodermatitis enteropathica (AE) and spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) are rare genetic skin disorders led by disturbed normal Zn homeostasis due to mutations of Zn transporters, ZIP4 and ZIP13, respectively. Recent mechanistic investigations into Zn´s functions help to develop new therapeutic approaches for the disorders. Areas covered: We reviewed the history, genetics, and current knowledge of pathogenic mechanism by mutated Zn transporter proteins for AE and SCD-EDS. We also discussed future prospects of therapeutics for these disorders. Expert opinion: Zn supplementation has already been recognized as a useful adjuvant for established therapies for a large number of dermatological disorders, improving quality of life of patients. Future challenge focusing on the development of modifiers for Zn transporter activity, gene or stem cell-based therapy may yield better therapeutics in combination with Zn treatment, and contribute to deeper understandings of the pathogenic mechanism behind Zn-associated skin diseases.

Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation.
Francesco Siracusa, Özen Sercan Alp, Patrick Maschmeyer, Mairi McGrath, Mir-Farzin Mashreghi, Shintaro Hojyo, Hyun-Dong Chang, Koji Tokoyoda, Andreas Radbruch
European journal of immunology, 47, 11, 1900, 1905, 2017年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, It is current belief that numbers of CD8+ memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here, we compare the proliferation of CD8+ memory T lymphocytes, generated by natural infections and by intentional immunization, in spleen and bone marrow (BM). Fifty percent of CD8+ memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8+ memory T lymphocytes are maintained by proliferation. The numbers of CD8+ memory T lymphocytes in the BM, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8+ memory T cells, blocked by FTY720, showing that BM is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation.

Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice.
Yongjuan Xin, Hong Gao, Jia Wang, Yuzhen Qiang, Mustapha Umar Imam, Yang Li, Jianyao Wang, Ruochen Zhang, Huizhen Zhang, Yingying Yu, Hao Wang, Haiyang Luo, Changhe Shi, Yuming Xu, Shintaro Hojyo, Toshiyuki Fukada, Junxia Min, Fudi Wang
Cell discovery, 3, 17025, 17025, 2017年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, SLC39A14 (also known as ZIP14), a member of the SLC39A transmembrane metal transporter family, has been reported to mediate the cellular uptake of iron and zinc. Recently, however, mutations in the SLC39A14 gene have been linked to manganese (Mn) accumulation in the brain and childhood-onset parkinsonism dystonia. It has therefore been suggested that SLC39A14 deficiency impairs hepatic Mn uptake and biliary excretion, resulting in the accumulation of Mn in the circulation and brain. To test this hypothesis, we generated and characterized global Slc39a14-knockout (Slc39a14
-/-
) mice and hepatocyte-specific Slc39a14-knockout (Slc39a14
fl/fl
;Alb-Cre
+
) mice. Slc39a14
-/-
mice develop markedly increased Mn concentrations in the brain and several extrahepatic tissues, as well as motor deficits that can be rescued by treatment with the metal chelator Na2CaEDTA. In contrast, Slc39a14
fl/fl
;Alb-Cre
+
mice do not accumulate Mn in the brain or other extrahepatic tissues and do not develop motor deficits, indicating that the loss of Slc39a14 expression selectively in hepatocytes is not sufficient to cause Mn accumulation. Interestingly, Slc39a14
fl/fl
;Alb-Cre
+
mice fed a high Mn diet have increased Mn levels in the serum, brain and pancreas, but not in the liver. Taken together, our results indicate that Slc39a14
-/-
mice develop brain Mn accumulation and motor deficits that cannot be explained by a loss of Slc39a14 expression in hepatocytes. These findings provide insight into the physiological role that SLC39A14 has in maintaining Mn homeostasis. Our tissue-specific Slc39a14-knockout mouse model can serve as a valuable tool for further dissecting the organ-specific role of SLC39A14 in regulating the body's susceptibility to Mn toxicity.

Zinc transporters and signaling in physiology and pathogenesis.
Shintaro Hojyo, Toshiyuki Fukada
Archives of biochemistry and biophysics, 611, 43, 50, 2016年12月01日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Zinc (Zn) is an essential trace element that is vital in a wide range of cellular machineries because of its effect on the expression and activity of various transcription factors and enzymes. Zn deficiency disturbs Zn homeostasis and has pathogenic consequences, including growth retardation and immune impairment in mammals. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the distribution, storage, and intracellular and extracellular concentration of Zn. Recent reverse-genetic approaches using Zn transporter-deficient mice have revealed the physiological functions of specific Zn signaling axes (each formed by Zn and a Zn transporter) in various biological programs. In this review, we describe recent discoveries about the role of Zn transporters which facilitate cellular signaling through Zn uptake in physiology and pathogenesis, with particular focus on the influence of Zn signaling in systemic growth and immunity.

Vaccination to gain humoral immune memory.
Jana Sarkander, Shintaro Hojyo, Koji Tokoyoda
Clinical & translational immunology, 5, 12, e120, 2016年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The concept of immune memory forms the biological basis for vaccination programs. Despite advancements in the field of immune memory and vaccination, most current vaccines are evaluated by magnitude of antigen-specific antibody titers in serum or mucosa after vaccination. It has been shown, however, that antibody-mediated humoral immune memory is established regardless of the magnitude and duration of immune reactions, suggesting that assessment of vaccine efficacy should be performed for several years after vaccination. This long-term investigation is disadvantageous for prevalent and pandemic infections. Long-lived memory plasma cells and memory helper T cells which contribute to humoral immune memory are generated in the bone marrow after migration of memory cell precursors through bloodstream. Thus, it may be a novel evaluation strategy to assess the precursors of memory cells in the blood in the early phase of the immune reaction(s). We here review recent advances on the generation and maintenance of immune memory cells involved in humoral immunity and introduce a current concept of direct and short-term assessment of humoral immune memory formation upon vaccination as a correlate of protection.

B Cells Negatively Regulate the Establishment of CD49b(+)T-bet(+) Resting Memory T Helper Cells in the Bone Marrow.
Shintaro Hojyo, Jana Sarkander, Christian Männe, Mathias Mursell, Asami Hanazawa, David Zimmel, Jinfang Zhu, William E Paul, Simon Fillatreau, Max Löhning, Andreas Radbruch, Koji Tokoyoda
Frontiers in immunology, 7, 26, 26, 2016年, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, During an immune reaction, some antigen-experienced CD4 T cells relocate from secondary lymphoid organs (SLOs) to the bone marrow (BM) in a CD49b-dependent manner and reside and rest there as professional memory CD4 T cells. However, it remains unclear how the precursors of BM memory CD4 T cells are generated in the SLOs. While several studies have so far shown that B cell depletion reduces the persistence of memory CD4 T cells in the spleen, we here show that B cell depletion enhances the establishment of memory CD4 T cells in the BM and that B cell transfer conversely suppresses it. Interestingly, the number of antigen-experienced CD4 T cells in the BM synchronizes the number of CD49b(+)T-bet(+) antigen-experienced CD4 T cells in the spleen. CD49b(+)T-bet(+) antigen-experienced CD4 T cells preferentially localize in the red pulp area of the spleen and the BM in a T-bet-independent manner. We suggest that B cells negatively control the generation of CD49b(+)T-bet(+) precursors of resting memory CD4 T cells in the spleen and may play a role in bifurcation of activated effector and resting memory CD4 T cell lineages.

Roles of Zinc Signaling in the Immune System.
Shintaro Hojyo, Toshiyuki Fukada
Journal of immunology research, 2016, 6762343, 6762343, 2016年, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Zinc (Zn) is an essential micronutrient for basic cell activities such as cell growth, differentiation, and survival. Zn deficiency depresses both innate and adaptive immune responses. However, the precise physiological mechanisms of the Zn-mediated regulation of the immune system have been largely unclear. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the transport, distribution, and storage of Zn. There is growing evidence that Zn behaves like a signaling molecule, facilitating the transduction of a variety of signaling cascades in response to extracellular stimuli. In this review, we highlight the emerging functional roles of Zn and Zn transporters in immunity, focusing on how crosstalk between Zn and immune-related signaling guides the normal development and function of immune cells.

SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis.
Supak Jenkitkasemwong, Chia-Yu Wang, Richard Coffey, Wei Zhang, Alan Chan, Thomas Biel, Jae-Sung Kim, Shintaro Hojyo, Toshiyuki Fukada, Mitchell D Knutson
Cell metabolism, 22, 1, 138, 50, 2015年07月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14(-/-) mice with Hfe(-/-) and Hfe2(-/-) mice, animal models of type 1 and type 2 (juvenile) hemochromatosis, respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.

Comparing gene expression during cadmium uptake and distribution: untreated versus oral Cd-treated wild-type and ZIP14 knockout mice.
Lucia F Jorge-Nebert, Marina Gálvez-Peralta, Julio Landero Figueroa, Maheshika Somarathna, Shintaro Hojyo, Toshiyuki Fukada, Daniel W Nebert
Toxicological sciences : an official journal of the Society of Toxicology, 143, 1, 26, 35, 2015年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The nonessential metal cadmium (Cd) is toxic only after entering the cell. Proteins possibly relevant to intracellular Cd accumulation include the divalent metal transporter-1 (DMT1) and all 14 zinc-like iron-like protein (ZIP) importers, 10 zinc transporter (ZnT) exporters, and metallothionein chaperones MT1 and MT2. Comparing oral Cd-treated ZIP14 knockout (KO) with wild-type (WT) mice, we predicted Cd uptake and distribution would be diminished in the KO-because ZIP14 is very highly expressed in GI tract and liver; this was indeed observed for Cd content in liver. However, the reverse was found in kidney and lung from 6 or 12 h through 10 days of Cd exposure; at these times, Cd accumulation was unexpectedly greater in KO than WT mice; mRNA levels of the 27 above-mentioned genes were thus examined in proximal small intestine (PSI) versus kidney to see if these paradoxical effects could be explained by substantial alterations in any of the other 26 genes. PSI genes highly expressed in untreated WT animals included seven ZIP and five ZnT transporters, DMT1, MT1, and MT2; kidney genes included 11 ZIP and 7 ZnT transporters, DMT1, MT1, and MT2. Over 10 days of oral Cd, a bimodal response was seen for Cd content in PSI and for various mRNAs; initially, acute effects caused by the toxic metal; subsequently, the up- or down-regulation of important genes presumably to combat the sustained adversity. These data underscore the complex interplay between the gastrointestinal tract and renal proteins that might be relevant to Cd uptake and distribution in animals exposed to oral Cd.

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development.
Tomohiro Miyai, Shintaro Hojyo, Tomokatsu Ikawa, Masami Kawamura, Tarou Irié, Hideki Ogura, Atsushi Hijikata, Bum-Ho Bin, Takuwa Yasuda, Hiroshi Kitamura, Manabu Nakayama, Osamu Ohara, Hisahiro Yoshida, Haruhiko Koseki, Kenji Mishima, Toshiyuki Fukada
Proceedings of the National Academy of Sciences of the United States of America, 111, 32, 11780, 5, 2014年08月12日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.

Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength.
Shintaro Hojyo, Tomohiro Miyai, Hitomi Fujishiro, Masami Kawamura, Takuwa Yasuda, Atsushi Hijikata, Bum-Ho Bin, Tarou Irié, Junichi Tanaka, Toru Atsumi, Masaaki Murakami, Manabu Nakayama, Osamu Ohara, Seiichiro Himeno, Hisahiro Yoshida, Haruhiko Koseki, Tomokatsu Ikawa, Kenji Mishima, Toshiyuki Fukada
Proceedings of the National Academy of Sciences of the United States of America, 111, 32, 11786, 91, 2014年08月12日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell-dependent and -independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.

Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.
Bum-Ho Bin, Shintaro Hojyo, Toshiaki Hosaka, Jinhyuk Bhin, Hiroki Kano, Tomohiro Miyai, Mariko Ikeda, Tomomi Kimura-Someya, Mikako Shirouzu, Eun-Gyung Cho, Kazuhisa Fukue, Taiho Kambe, Wakana Ohashi, Kyu-Han Kim, Juyeon Seo, Dong-Hwa Choi, Yeon-Ju Nam, Daehee Hwang, Ayako Fukunaka, Yoshio Fujitani, Shigeyuki Yokoyama, Andrea Superti-Furga, Shiro Ikegawa, Tae Ryong Lee, Toshiyuki Fukada
EMBO molecular medicine, 6, 8, 1028, 42, 2014年08月, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13(G64D), in which Gly at amino acid position 64 is replaced by Asp, and ZIP13(ΔFLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(ΔFLA) protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS.

Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) and the mutant zinc transporter ZIP13.
Bum-Ho Bin, Shintaro Hojyo, Tae Ryong Lee, Toshiyuki Fukada
Rare diseases (Austin, Tex.), 2, 1, e974982, 2014年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The zinc transporter protein ZIP13 plays crucial roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). We recently reported that the pathogenic mutations in ZIP13 reduce its functional protein level by accelerating the protein degradation via the VCP-linked ubiquitin proteasome pathway, resulting in the disturbance of intracellular zinc homeostasis that appears to contribute to SCD-EDS pathogenesis. Finally, we implicate that possible therapeutic approaches for SCD-EDS would be based on regulating the degradation of the pathogenic mutant ZIP13 proteins.

The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.
Motoyuki Tamaki, Yoshio Fujitani, Akemi Hara, Toyoyoshi Uchida, Yoshifumi Tamura, Kageumi Takeno, Minako Kawaguchi, Takahiro Watanabe, Takeshi Ogihara, Ayako Fukunaka, Tomoaki Shimizu, Tomoya Mita, Akio Kanazawa, Mica O Imaizumi, Takaya Abe, Hiroshi Kiyonari, Shintaro Hojyo, Toshiyuki Fukada, Takeshi Kawauchi, Shinya Nagamatsu, Toshio Hirano, Ryuzo Kawamori, Hirotaka Watada
The Journal of clinical investigation, 123, 10, 4513, 24, 2013年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.

ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders.
Hyeyoung Nam, Chia-Yu Wang, Lin Zhang, Wei Zhang, Shintaro Hojyo, Toshiyuki Fukada, Mitchell D Knutson
Haematologica, 98, 7, 1049, 57, 2013年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The liver, pancreas, and heart are particularly susceptible to iron-related disorders. These tissues take up plasma iron from transferrin or non-transferrin-bound iron, which appears during iron overload. Here, we assessed the effect of iron status on the levels of the transmembrane transporters, ZRT/IRT-like protein 14 and divalent metal-ion transporter-1, which have both been implicated in transferrin- and non-transferrin-bound iron uptake. Weanling male rats (n=6/group) were fed an iron-deficient, iron-adequate, or iron-overloaded diet for 3 weeks. ZRT/IRT-like protein 14, divalent metal-ion transporter-1 protein and mRNA levels in liver, pancreas, and heart were determined by using immunoblotting and quantitative reverse transcriptase polymerase chain reaction analysis. Confocal immunofluorescence microscopy was used to localize ZRT/IRT-like protein 14 in the liver and pancreas. ZRT/IRT-like protein 14 and divalent metal-ion transporter-1 protein levels were also determined in hypotransferrinemic mice with genetic iron overload. Hepatic ZRT/IRT-like protein 14 levels were found to be 100% higher in iron-loaded rats than in iron-adequate controls. By contrast, hepatic divalent metal-ion transporter-1 protein levels were 70% lower in iron-overloaded animals and nearly 3-fold higher in iron-deficient ones. In the pancreas, ZRT/IRT-like protein 14 levels were 50% higher in iron-overloaded rats, and in the heart, divalent metal-ion transporter-1 protein levels were 4-fold higher in iron-deficient animals. At the mRNA level, ZRT/IRT-like protein 14 expression did not vary with iron status, whereas divalent metal-ion transporter-1 expression was found to be elevated in iron-deficient livers. Immunofluorescence staining localized ZRT/IRT-like protein 14 to the basolateral membrane of hepatocytes and to acinar cells of the pancreas. Hepatic ZRT/IRT-like protein 14, but not divalent metal-ion transporter-1, protein levels were elevated in iron-loaded hypotransferrinemic mice. In conclusion, ZRT/IRT-like protein 14 protein levels are up-regulated in iron-loaded rat liver and pancreas and in hypotransferrinemic mouse liver. Divalent metal-ion transporter-1 protein levels are down-regulated in iron-loaded rat liver, and up-regulated in iron-deficient liver and heart. Our results provide insight into the potential contributions of these transporters to tissue iron uptake during iron deficiency and overload.

Zinc signal: a new player in osteobiology.
Toshiyuki Fukada, Shintaro Hojyo, Tatsuya Furuichi
Journal of bone and mineral metabolism, 31, 2, 129, 35, 2013年03月, ［査読有り］, ［招待有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Disturbed zinc (Zn) homeostasis in mammals is mainly characterized by impaired bone generation accompanied with growth retardation. However, the underlying mechanisms that determine how Zn controls bone homeostasis remain to be defined. Zn homeostasis is tightly controlled by Zn transporter families. Recent studies have shown that Zn transporter-mediated Zn ion (Zn(2+)) behaves as a signaling factor, called Zn signal, that exerts a multiple function in cellular events, showing why Zn has a vital effect on mammalian bone growth and regeneration. This perspective put importance on the principal mechanisms of Zn participation in mammalian bone homeostasis, shifting our focus on the role of Zn from simply a nutrient to a signaling molecule that fine-tunes intracellular signaling events.

[Zinc signaling : a novel regulatory system on bone homeostasis, and immune and allergic responses].
Toshiyuki Fukada, Keigo Nishida, Satoru Yamasaki, Shintaro Hojyo
Clinical calcium, 22, 11, 1707, 27, 2012年11月, ［査読有り］, ［招待有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Zinc (Zn) is an essential trace element that is required for proliferation, differentiation, and variety of cellular functions, and unbalanced homeostasis of Zn ion (Zn(2 + )) results in health problems such as abnormal bone formation and immunodeficiency. Recent studies have shed light on important roles of Zn(2 + )as a signaling mediator, called Zn signal. Zn(2 + )homeostasis is regulated through Zn transporters and cation channels. Advances of genetic and molecular approaches have revealed that Zn signal regulates mammalian physiology and pathogenesis. We will address that Zn signal undoubtedly contributes to our health, by highlighting it in bone homeostasis and immune regulation, and discuss that the "Zn signal axis" selectively controls intracellular signal transduction to fine-tune cellular functions.

【骨免疫学〜基礎と臨床〜】亜鉛シグナル 新しい骨代謝と免疫・アレルギー応答の制御システム
深田 俊幸, 西田 圭吾, 山崎 哲, 北條 慎太郎
Clinical Calcium, 22, 11, 1707, 1727, (株)医薬ジャーナル社, 2012年10月, ［査読有り］, ［招待有り］
日本語, 亜鉛は生命活動に必要とされる必須微量元素の一つであり、約半世紀前に発見された亜鉛欠乏症が契機となって様々な細胞機能における亜鉛の多様な関与が示されている。亜鉛イオンの恒常性は亜鉛トランスポーターやカチオンチャネルが制御しており、最近の研究によって哺乳類の初期発生、全身成長、硬組織形成、生体防御機能などにおける亜鉛イオンの恒常性の意義が分子レベルで明らかになりつつある。本総説では、亜鉛トランスポーターやカチオンチャネルが輸送する亜鉛イオンがシグナル因子(亜鉛シグナル)として機能すること、この亜鉛シグナルが骨軟骨代謝や免疫・アレルギー応答に深く関わることを、その破綻に起因する疾患症例とともに紹介する。さらに、なぜ亜鉛シグナルに特異性があるのか、その機序の一つとして筆者らが提唱する『亜鉛シグナル機軸』について議論する。(著者抄録)

A novel role of the L-type calcium channel α1D subunit as a gatekeeper for intracellular zinc signaling: zinc wave.
Satoru Yamasaki, Aiko Hasegawa, Shintaro Hojyo, Wakana Ohashi, Toshiyuki Fukada, Keigo Nishida, Toshio Hirano
PloS one, 7, 6, e39654, 2012年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent studies have shown that zinc ion (Zn) can behave as an intracellular signaling molecule. We previously demonstrated that mast cells stimulated through the high-affinity IgE receptor (FcεRI) rapidly release intracellular Zn from the endoplasmic reticulum (ER), and we named this phenomenon the "Zn wave". However, the molecules responsible for releasing Zn and the roles of the Zn wave were elusive. Here we identified the pore-forming α(1) subunit of the Cav1.3 (α(1D)) L-type calcium channel (LTCC) as the gatekeeper for the Zn wave. LTCC antagonists inhibited the Zn wave, and an agonist was sufficient to induce it. Notably, α(1D) was mainly localized to the ER rather than the plasma membrane in mast cells, and the Zn wave was impaired by α(1D) knockdown. We further found that the LTCC-mediated Zn wave positively controlled cytokine gene induction by enhancing the DNA-binding activity of NF-κB. Consistent with this finding, LTCC antagonists inhibited the cytokine-mediated delayed-type allergic reaction in mice without affecting the immediate-type allergic reaction. These findings indicated that the LTCC α(1D) subunit located on the ER membrane has a novel function as a gatekeeper for the Zn wave, which is involved in regulating NF-κB signaling and the delayed-type allergic reaction.

Biochemical characterization of human ZIP13 protein: a homo-dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers-Danlos syndrome.
Bum-Ho Bin, Toshiyuki Fukada, Toshiaki Hosaka, Satoru Yamasaki, Wakana Ohashi, Shintaro Hojyo, Tomohiro Miyai, Keigo Nishida, Shigeyuki Yokoyama, Toshio Hirano
The Journal of biological chemistry, 286, 46, 40255, 65, 2011年11月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The human SLC39A13 gene encodes ZIP13, a member of the LZT (LIV-1 subfamily of ZIP zinc transporters) family. The ZIP13 protein is important for connective tissue development, and its loss of function is causative for the spondylocheiro dysplastic form of Ehlers-Danlos syndrome. However, this protein has not been characterized in detail. Here we report the first detailed biochemical characterization of the human ZIP13 protein using its ectopic expressed and the purified recombinant protein. Protease accessibility, microscopic, and computational analyses demonstrated that ZIP13 contains eight putative transmembrane domains and a unique hydrophilic region and that it resides with both its N and C termini facing the luminal side on the Golgi. Analyses including cross-linking, immunoprecipitation, Blue Native-PAGE, and size-exclusion chromatography experiments indicated that the ZIP13 protein may form a homo-dimer. We also demonstrated that ZIP13 mediates zinc influx, as assessed by monitoring the expression of the metallothionein gene and by detecting the intracellular zinc level with a zinc indicator, FluoZin-3. Our data indicate that ZIP13 is a homo-dimerized zinc transporter that possesses some domains that are not found in other LZT family members. This is the first biochemical characterization of the physiologically important protein ZIP13 and the demonstration of homo-dimerization for a mammalian ZIP zinc transporter family member. This biochemical characterization of the human ZIP13 protein provides important information for further investigations of its structural characteristics and function.

The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth.
Shintaro Hojyo, Toshiyuki Fukada, Shinji Shimoda, Wakana Ohashi, Bum-Ho Bin, Haruhiko Koseki, Toshio Hirano
PloS one, 6, 3, e18059, 2011年03月22日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Aberrant zinc (Zn) homeostasis is associated with abnormal control of mammalian growth, although the molecular mechanisms of Zn's roles in regulating systemic growth remain to be clarified. Here we report that the cell membrane-localized Zn transporter SLC39A14 controls G-protein coupled receptor (GPCR)-mediated signaling. Mice lacking Slc39a14 (Slc39a14-KO mice) exhibit growth retardation and impaired gluconeogenesis, which are attributable to disrupted GPCR signaling in the growth plate, pituitary gland, and liver. The decreased signaling is a consequence of the reduced basal level of cyclic adenosine monophosphate (cAMP) caused by increased phosphodiesterase (PDE) activity in Slc39a14-KO cells. We conclude that SLC39A14 facilitates GPCR-mediated cAMP-CREB signaling by suppressing the basal PDE activity, and that this is one mechanism for Zn's involvement in systemic growth processes. Our data highlight SLC39A14 as an important novel player in GPCR-mediated signaling. In addition, the Slc39a14-KO mice may be useful for studying the GPCR-associated regulation of mammalian systemic growth.

Zinc suppresses Th17 development via inhibition of STAT3 activation.
Chika Kitabayashi, Toshiyuki Fukada, Minoru Kanamoto, Wakana Ohashi, Shintaro Hojyo, Toru Atsumi, Naoko Ueda, Ichiro Azuma, Hiroshi Hirota, Masaaki Murakami, Toshio Hirano
International immunology, 22, 5, 375, 86, 2010年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Zinc (Zn) is an essential trace metal required by many enzymes and transcription factors for their activity or the maintenance of their structure. Zn has a variety of effects in the immune responses and inflammation, although it has not been well known how Zn affects these reactions on the molecular basis. We here showed that Zn suppresses T(h)17-mediated autoimmune diseases at lest in part by inhibiting the development of T(h)17 cells via attenuating STAT3 activation. In mice injected with type II collagen to induce arthritis, Zn treatment inhibited T(h)17 cell development. IL-6-mediated activation of STAT3 and in vitro T(h)17 cell development were all suppressed by Zn. Importantly, Zn binding changed the alpha-helical secondary structure of STAT3, disrupting the association of STAT3 with JAK2 kinase and with a phospho-peptide that included a STAT3-binding motif from the IL-6 signal transducer gp130. Thus, we conclude that Zn suppresses STAT3 activation, which is a critical step for T(h)17 development.

The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways.
Toshiyuki Fukada, Natacha Civic, Tatsuya Furuichi, Shinji Shimoda, Kenji Mishima, Hiroyuki Higashiyama, Yayoi Idaira, Yoshinobu Asada, Hiroshi Kitamura, Satoru Yamasaki, Shintaro Hojyo, Manabu Nakayama, Osamu Ohara, Haruhiko Koseki, Heloisa G Dos Santos, Luisa Bonafe, Russia Ha-Vinh, Andreas Zankl, Sheila Unger, Marius E Kraenzlin, Jacques S Beckmann, Ichiro Saito, Carlo Rivolta, Shiro Ikegawa, Andrea Superti-Furga, Toshio Hirano
PloS one, 3, 11, e3642, 2008年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. CONCLUSIONS/SIGNIFICANCE: Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function.
Hidemitsu Kitamura, Hideyuki Morikawa, Hokuto Kamon, Megumi Iguchi, Shintaro Hojyo, Toshiyuki Fukada, Susumu Yamashita, Tsuneyasu Kaisho, Shizuo Akira, Masaaki Murakami, Toshio Hirano
Nature immunology, 7, 9, 971, 7, 2006年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.

Characterization and expression analysis of a chicken interleukin-6 receptor alpha.
Norihisa Nishimichi, Tsuyoshi Kawashima, Shintaro Hojyo, Hiroyuki Horiuchi, Shuichi Furusawa, Haruo Matsuda
Developmental and comparative immunology, 30, 4, 419, 29, 2006年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Interleukin-6 (IL-6) is a multifunctional cytokine that plays roles in regulating immune responses, acute phase reactions and hematopoiesis. IL-6 signaling is regulated by two receptors, a specific alpha chain (IL-6Ralpha) and a signal transducer, gp130. In this study, cDNA encoding the 445 amino acid propeptide of chicken IL-6Ralpha (chIL-6Ralpha) was identified. The predicted 445 amino acids showed approximately 40% sequence identity with mammalian homologues. In a domain search, chIL-6Ralpha had a signal peptide of 20 residues, an immunoglobulin-like (IG) domain of 71 residues and a fibronectin-type III (FN III) domain of 85 residues. On comparison with mammalian homologues, four conserved cysteine residues and the WSXWS motif were observed in the N- and C-terminal regions of the FN III domain, respectively. Expression analysis revealed that chIL-6Ralpha is strongly expressed in liver and the chicken hepatoma cell line LMH. These findings indicate that the identified chicken cDNA sequence encodes a chIL-6Ralpha homologue.

Characterization and expression analysis of the chicken interleukin-11 receptor alpha chain.
Tsuyoshi Kawashima, Shintaro Hojyo, Norihisa Nishimichi, Masaharu Sato, Masayoshi Aosasa, Hiroyuki Horiuchi, Shuichi Furusawa, Haruo Matsuda
Developmental and comparative immunology, 29, 4, 349, 59, 2005年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Interleukin-11 (IL-11) is a multifunctional cytokine involved in various pathways in blood cells, their precursors and many other cell types in vitro and in vivo. The effects of IL-11 are largely mediated by the IL-11 receptor alpha-chain (IL-11Ralpha). In this study, a putative cDNA sequence encoding the 414 amino acid propeptide of chicken IL-11R (chIL-11R) was identified. The predicted 414 amino acid sequence showed 42-43% sequence identity with mammalian homologues. In a domain search of the molecule, two fibronectin (FN) type-III domains were identified in the C- terminal portion. On comparison with mammalian IL-11R, 4 conserved cysteine residues and a WSXWS motif were observed within the FN type-III domains. Expression analysis revealed that chIL-11Ralpha is strongly expressed in brain, heart, lung, liver, glandular stomach, kidney, the immature testis, ovary and chicken blastodermal cells (CBCs) after 1-day-cultivation. These findings strongly indicate that the identified chicken cDNA sequence encodes chIL-11R alpha-chain homologue.

ニワトリ型単クローン抗体を用いた肝細胞癌の診断
甲田 徹三, 北條 慎太郎
医療, 58, 8, 470, 476, (一社)国立医療学会, 2004年08月, ［査読有り］
日本語, ニワトリ抗NeuGcモノクロナール抗体(HU/Ch6-1)を用いて,肝細胞癌の組織中・患者血清中のNeuGcについて検討した.その結果,摘出肝細胞癌組織37例中17例(45.9%)に糖脂質型NeuGcの発現を認めた.肝細胞癌患者血清中では,25例(67.6%)にIgG型またはIgM型NeuGc抗体の上昇が確認された.なお,血清中のNeuGc抗体とAFP,PIVKA-II値との間に相関は示されなかった.以上より,ニワトリ抗NeuGcモノクロナール抗体は肝細胞癌の診断に有用である可能性が示唆された

ほ乳動物プリオンプロテインを認識するニワトリモノクローナル抗体パネルの樹立(Establishment of a Chicken Monoclonal Antibody Panel Against Mammalian Prion Protein)
中村 尚登, 朱山 亜希, 北條 慎太郎, 下川 摩里子, 宮本 和慶, 川嶋 剛, 青笹 正義, 堀内 浩幸, 古澤 修一, 松田 治男
The Journal of Veterinary Medical Science, 66, 7, 807, 814, (公社)日本獣医学会, 2004年07月, ［査読有り］, ［国内誌］
英語, A panel of chicken monoclonal antibodies (mAbs) was developed against prion protein (PrP), the sequence of which is a highly conserved molecule among mammals. A portion of the splenocytes from chickens immunized with recombinant mouse PrP was fused with the chicken B cell line, MuH1. The remaining splenocytes were used to generate the recombinant mAbs by phage display. A total of 36 anti-PrP mAbs, 2 from cell fusion and 34 from phage display were established. The specificity of these mAbs was determined by Western blot and ELISA using various PrP antigens including recombinant PrPs, synthetic PrP peptides and PrPs from brains or scrapie-infected neuroblastoma cell line. These mAbs were classified into three main groups, protease K (PK)-sensitive (Group I), PK cleavage site proximal (Group II) and PK-resistant (Group III), based on their abilities to recognize PrP following PK-treatment. Some mAbs were found to selectively recognize different glycoforms of PrP as well as the metabolic fragments of PrP. Furthermore, we found that PrP recognition by chickens differed from that by PrP-knockout mouse. These results indicate that these newly generated PrP antibodies from chickens will help to research the PrP and to establish the diagnosis of prion disease.

Two expression vectors for the phage-displayed chicken monoclonal antibody.
Naoto Nakamura, Mariko Shimokawa, Kazuyoshi Miyamoto, Shintaro Hojyo, Hiroyuki Horiuchi, Shuichi Furusawa, Haruo Matsuda
Journal of immunological methods, 280, 1-2, 157, 64, 2003年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We previously reported the development of chicken monoclonal antibodies (mAb) against mammalian-conserved molecules by cell fusion and phage display using the mouse mAb expression vector pPDS. However, chicken hybridomas produce relatively small amounts of antibody when compared with mouse hybridomas, and application of the pPDS may be limited in two-antibody assays with a mouse mAb because it contains mouse Ckappa as a detection tag. To circumvent the above problems, two expression vectors were established and used to produce a functional recombinant chicken mAb. These vectors, which were designed to accommodate a single chain fragment of the variable region (scFv) of the antibody, contained a chicken Clambda and FLAG with or without 6 x histidine sequences in the 3' terminus of the scFv to serve as detection and purification tags. In this study, a prion protein (PrP)-specific chicken mAb (HUC2-13) was expressed as phage-displayed and soluble scFv mAb forms by using these vectors. The scFv mAbs expressed by these vectors exhibited the same antigen-binding specificity to PrP as that of the original HUC2-13, could be purified with ease, and used in combination with a mouse mAb. These results indicate that the methods described herein offer an alternative to chicken mAb production from hybridomas and immunized chicken splenocytes, and may contribute to the use of chicken mAb reagents in numerous fields.

神経系と免疫の接点 第12回 ゲートウェイ反射による中枢炎症制御
山崎剛士, 田中宏樹, 長谷部理絵, 北條慎太郎, 炎症と免疫, 32, 2, 2024年

【自己免疫疾患 層別化する新時代へ 臨床検体のマルチオミクス解析、腸内細菌によって見えてきた免疫経路の全容】(第2章)自己免疫疾患の基盤メカニズムの最新知見 ゲートウェイ反射による自己免疫疾患の制御　　　　　　　　　　　　　　　
村上 薫, 西 李依子, 北條 慎太郎, 田中 勇希, 村上 正晃, 実験医学, 40, 15, 2456, 2466, 2022年09月
計測技術、解析技術の進歩に伴い神経免疫学は日進月歩の分野となった。そのなかでもわれわれは自己免疫疾患を含む炎症性疾患の発症について、非免疫細胞においてNF-κBとSTAT3が同時に活性化されることでNF-κB経路の過剰な活性化が惹起され、サイトカイン、ケモカイン、および成長因子などの炎症性メディエーターの産生が相乗的かつ局所的に増強する「IL-6アンプ」と、特定の血管領域においてIL-6アンプを誘導するために必要な特異的な神経回路の活性化機構である「ゲートウェイ反射」を発見した。本稿では、最近我々が発表した、RAに新規の診断・治療標的をもたらす遠隔炎症ゲートウェイ反射を含む各ゲートウェイについて概説する。(著者抄録), (株)羊土社, 日本語

多発性硬化症モデル動物におけるMaresin-1の保護効果　　　　　　　　　　　　　　　
菅原 季起, 田中 勇希, 北條 慎太郎, 村上 正晃, 南 雅文, 日本薬学会年会要旨集, 142年会, 27F, pm10S, 2022年03月
(公社)日本薬学会, 日本語

COVID-19における非免疫細胞によるサイトカインストーム発症機構
北條 慎太郎, BIO-EX-press, 2022年冬号, 12, 17, 2022年

【免疫系の暴走 サイトカインストーム 多様な疾患で生じる全身性の炎症反応その共通機構から病態を理解する】IL-6アンプとCOVID-19におけるサイトカインストーム誘導機構
内田 萌菜, 田中 くみ子, 北條 慎太郎, 田中 勇希, 長谷部 理絵, 村上 正晃, 実験医学, 39, 4, 499, 504, 2021年03月
2021年1月8日、イギリス政府は、IL-6受容体に対する2種類の中和抗体であるトシリズマブとサリルマブが、新型コロナウイルス感染症(COVID-19)の重症患者の治療に有効であると発表した。本発表は重篤化したCOVID-19の病態形成にIL-6シグナルが関与していることを示すものであり、重篤化の本態であるサイトカインストームとの関連性を示唆するものである。COVID-19の重症化には、サイトカインストームの引き金である活性化T細胞に加えて、肺胞上皮細胞や血管内皮細胞などの非免疫細胞におけるIL-6アンプが関連していると考えられる。本稿では、今後さまざまな病態でのサイトカインストームの治療標的として注目されるであろうIL-6アンプについて、その誘導機構を解説する。(著者抄録), (株)羊土社, 日本語

【コロナウイルス感染の免疫学】サイトカインストームとIL-6アンプ
北條 慎太郎, 炎症と免疫, 30巻1号, 1, 18, 27, 2021年
昨今、新型コロナウイルス(Severe acute respiratory syndrome coronavirus 2:SARS-CoV-2)が世界中で猛威を振るっている。11月1日現在、累計の患者数は2億5,000万人、死者は500万人となっており、ワクチンが各国の国民に接種されてなお、変異型がつぎつぎ登場するこのウイルスによるパンデミックは終わる様相をみせない。SARS-CoV-2の最も恐ろしい点は、高齢者や基礎疾患のある人に対する重症化からの多臓器不全による死亡だ。これには免疫系の暴走とも評されるサイトカインストームが深くかかわっている。サイトカインストームを引き起こす原因の一つに免疫系細胞の過剰活性化とあわせて非免疫細胞における核内因子κB(nuclear factor-kappa B:NF-κB)の過剰活性化機構であるインターロイキン-6(IL-6)アンプが知られており、サイトカインストーム、ひいてはSARS-CoV-2の病態の理解のためには、まずIL-6アンプの理解も大切だろう。(著者抄録), (株)先端医学社, 日本語

ATPによる感覚神経-介在神経回路の活性化は遠隔部位での炎症反応を誘導する
長谷部理絵, 田中勇希, 北條慎太郎, 村上正晃, 日本インターフェロン・サイトカイン学会学術集会抄録集, 85th (CD-ROM), 2021年

COVID-19 サイトカインストームとリンパ球機能
北條 慎太郎, 内田 萌菜, 田中 くみ子, 長谷部 理絵, 村上 正晃, 臨床免疫・アレルギー科, 75, 1, 94, 100, 2021年01月
(有)科学評論社, 日本語

新型コロナウイルス感染症(COVID-19)におけるサイトカインストーム
高橋 郁子, 木田 博朗, 田中 くみ子, 北條 慎太郎, 長谷部 理絵, 村上 正晃, 老年内科, 3, 1, 74, 82, 2021年01月
(有)科学評論社, 日本語

【新型コロナウイルス感染症(COVID-19)-私たちが今知っておくべきこと】新型コロナウイルス感染症(COVID-19)重症化のメカニズム
長谷部 理絵, 北條 慎太郎, 田中 勇希, 内田 萌菜, 村上 正晃, カレントテラピー, 38, 12, 1145, 1150, 2020年12月
新型コロナウイルス感染症(COVID-19)では、患者の多くは無症候または軽度の症状を示した後に回復するが、一部の患者は急性呼吸窮迫症候群(acute respiratory distress syndrome:ARDS)、多臓器不全などの重度の症状を示し、死亡する。重症化患者では血中サイトカインレベルが上昇しており、特に血中IL-6レベルは死亡率と相関があることから、致死性のCOVID-19は、IL-6を基軸とするサイトカインストームが引き起こすcytokine releasing syndromeであると考えられる。新型コロナウイルス感染を起点とするサイトカインストームの誘導には、肺胞上皮細胞や血管内皮細胞などの非免疫細胞でSTAT3/NF-κBシグナルの同時活性化により、NF-κBの過剰活性化が起こるIL-6アンプが関連しているものと考えられ、IL-6シグナリングの阻害は、重症COVID-19の治療標的の有力な候補のひとつとして挙げられる。(著者抄録), (株)ライフメディコム, 日本語

【線維化 慢性疾患のキープロセス 多彩な間質細胞が織りなす組織リモデリング"fibrosis"の理解】(第2章)線維化を制御する細胞間ネットワーク 炎症の誘導機構 IL-6アンプの病気への関与
北條 慎太郎, 内田 萌菜, 村上 薫, 松山 詩菜, 田中 くみ子, 村上 正晃, 実験医学, 38, 12, 2032, 2039, 2020年08月
線維化には炎症の誘導が伴う。われわれはIL-6サイトカインと関節リウマチモデルの研究を通して炎症誘導の基盤的機構であるIL-6アンプを発見し、その分子機序について研究を続けている。その過程で、特異的な血管部のIL-6アンプが血液脳関門に免疫細胞の侵入口を形成することを発見し、ゲートウェイ反射と名付けた。本稿では、これら一連の研究を紹介する。(著者抄録), (株)羊土社, 日本語

自己免疫疾患における濾胞制御性T細胞の役割
北條 慎太郎, ファルマシア, 54, 9, 902, 902, 2018年09月
体液性免疫は獲得免疫における主要な機構であり，ウイルス・細菌感染に対するB細胞の抗体産生を主軸とした免疫系を指す．体液性免疫応答の過程において，B細胞はヘルパーT細胞からサイトカインや補助刺激シグナルを受けて胚中心(germinal center：GC)とよばれる特殊な構造体を二次リンパ組織上に構築する．さらにGC B細胞は体細胞突然変異とクラススイッチを経て，抗原に対して高い親和性を有する記憶B細胞や長期的に生存可能な抗体産生細胞へと分化する(GC反応)．GC B細胞の分化には濾胞ヘルパーT(t follicular helper：Tfh)細胞(転写因子Bcl6，ケモカイン受容体CXCR5，アポトーシス関連タンパクPD-1共陽性)との相互作用が必須であり，Tfh細胞の細胞数が厳密に制御されることにより自己寛容が誘導される．逆に，自己反応性のTfh細胞の増多は自己免疫疾患の発症と関連する．
最近，胚中心に認められるTfh細胞集団の中に，免疫系を負に制御することで知られる制御性T細胞(転写因子Foxp3陽性)の特徴を有する濾胞制御性T(t follicular regulatory：Tfr)細胞とよばれる新規の細胞亜集団が発見され，脚光を浴びている．このTfr細胞は，in vivoにおいてGC反応を負に制御することが知られているが，これまでTfr細胞の病理学的な役割は不明であった．本稿では，Fuらによって報告されたTfr細胞による自己免疫疾患の制御に関わる知見を紹介する．
なお，本稿は下記の文献に基づいて，その研究成果を紹介するものである.
1) Chung Y. et al., Nat. Med., 17, 983-988(2011)．
2) Linterman M. A. et al., Nat. Med., 17, 975-982(2011)．
3) Fu W. et al., J. Exp. Med., 215, 815-825(2018)．, 公益社団法人 日本薬学会, 日本語

B cells influence on an environmental cue for IL-2-dependent generation of resting memory T helper cells
S. Hojyo, J. Sarkander, T. Y. Wu, M. Mursell, A. Radbruch, M. Loehning, K. Tokoyoda, EUROPEAN JOURNAL OF IMMUNOLOGY, 47, 272, 272, 2017年12月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

ZIP10を介した亜鉛シグナル伝達はB細胞の維持と獲得免疫に必要である(ZIP10-mediated zinc signaling is required for B-cell maintenance and acquired immunity)　　　　　　　　　　　　　　　
深田 俊幸, 宮井 智浩, 北條 慎太郎, 賓 範浩, 入江 太朗, 田中 準一, 美島 健二, 日本病理学会会誌, 104, 1, 381, 381, 2015年03月
(一社)日本病理学会, 英語

B-cell receptor strength and zinc signaling: Unraveling the role of zinc transporter ZIP10 in humoral immunity　　　　　　　　　　　　　　　
Shintaro Hojyo, Tomohiro Miyai, Toshiyuki Fukada, Receptors & Clinical Investigation, 2, e387, 2015年, ［招待有り］
英語, 記事・総説・解説・論説等（学術雑誌）

ノックアウトマウスから明らかとなった亜鉛トランスポーターZIP14による骨量制御メカニズム　　　　　　　　　　　　　　　
佐々木 俊, 北條 慎太郎, 深田 俊幸, 古市 達哉, 日本獣医学会学術集会講演要旨集, 157回, 539, 539, 2014年08月
(公社)日本獣医学会, 日本語

【骨代謝 つくり、壊し、変える-そのメカニズムと最新治療 分子機構から骨粗鬆症・リウマチなど骨疾患への応用まで】(第II部) 骨代謝疾患を知る (第5章)骨の疾患 原因からみた骨代謝異常 亜鉛シグナルによる骨代謝制御とその破綻がもたらす異常
北條 慎太郎, 賓 範浩, 深田 俊幸, 実験医学, 32, 7, 1108, 1118, 2014年05月, ［査読有り］
亜鉛は食物や飲料から摂取される必須微量元素であり、その成長や骨代謝における重要性が認識される契機となったのは約半世紀前にさかのぼる「亜鉛欠乏症」の発見である。亜鉛の欠乏は成長遅延や骨粗鬆症、免疫不全をはじめとした多種多様な疾患を引き起こし、現在では亜鉛は細胞が正常に機能するために必要不可欠な重金属として位置づけられている。亜鉛の恒常性は亜鉛トランスポーターによって厳密に制御されており、その遺伝子改変マウスを用いた最近の研究から亜鉛トランスポーターを介して輸送される亜鉛がシグナル因子として機能し(亜鉛シグナル)、さまざまな生命現象を制御している様相が解明されつつある。本稿では、亜鉛シグナルが成長や骨代謝に関与する特定のシグナル伝達経路を制御し、その破綻が疾患発症にリンクすることを、遺伝子改変マウスの解析から得られた知見をもとに概説する。(著者抄録), (株)羊土社, 日本語

亜鉛トランスポーターSLC39A10/ZIP10は、B細胞受容体シグナル伝達を介した成熟B細胞の恒常性維持と体液性免疫応答を制御する　　　　　　　　　　　　　　　
北條 慎太郎, 深田 俊幸, 古関 明彦, 平野 俊夫, 日本生化学会大会プログラム・講演要旨集, 86回, 3T13p, 09, 2013年09月
(公社)日本生化学会, 日本語

亜鉛トランスポーター欠損マウスを用いた亜鉛による骨量制御機構の研究　　　　　　　　　　　　　　　
古市 達哉, 佐々木 俊, 市村 鋭, 北條 慎太郎, 深田 俊幸, 日本獣医学会学術集会講演要旨集, 156回, 396, 396, 2013年08月
(公社)日本獣医学会, 日本語

シグナル伝達を理解するために必要な知識(第38回)(No.76) 亜鉛によるシグナル伝達 「亜鉛シグナル」とは
大橋 若奈, 北條 慎太郎, 深田 俊幸, 分子消化器病, 10, 2, 189, 196, 2013年06月, ［査読有り］
(株)先端医学社, 日本語

ZIP14 KNOCKOUT MICE EXHIBIT ALTERED IRON METABOLISM AND MARKEDLY IMPAIRED HEPATIC AND PANCREATIC UPTAKE OF INTRAVENOUSLY ADMINISTERED NON-TRANSFERRIN-BOUND IRON
Supak Jenkitkasemwong, Chia-Yu Wang, Shintaro Hojyo, Toshiyuki Fukada, Mitchell Knutson, AMERICAN JOURNAL OF HEMATOLOGY, 88, 5, E10, E11, 2013年05月
WILEY-BLACKWELL, 英語, 研究発表ペーパー・要旨（国際会議）

亜鉛シグナル 健康と疾患を統御する新しい情報伝達システム
北條 慎太郎, 深田 俊幸, バイオサイエンスとインダストリー, 71, 1, 8, 13, 2013年01月, ［査読有り］
亜鉛は必須微量元素の1つである。亜鉛の恒常性は亜鉛トランスポーターによって制御され、哺乳類の初期発生、全身成長、免疫系などに深く関与している。本稿では、亜鉛トランスポーターが輸送する亜鉛イオンがシグナル因子として機能すること(亜鉛シグナル)、この亜鉛シグナルが免疫・アレルギー応答や骨軟骨代謝に深く関与することを、その破綻に起因する疾患症例とともに紹介する。(著者抄録), (一財)バイオインダストリー協会, 日本語

【骨代謝研究の最近のトピックス-基礎と臨床-】亜鉛イオンによる新しい骨代謝制御機序 "亜鉛シグナル機軸"
深田 俊幸, 北條 慎太郎, THE BONE, 26, 2, 221, 232, 2012年04月, ［査読有り］
亜鉛は生命活動に必要とされる必須微量元素の一つであり、約半世紀前に発見された「亜鉛欠乏症」がきっかけとなって、ヒトの健康と疾患における亜鉛の多様な関与が示されている。細胞における亜鉛イオンの恒常性は亜鉛トランスポーターが維持しており、最近の亜鉛トランスポーター研究によって哺乳類の初期発生、全身成長、骨格形成、皮膚代謝、生体防御機能などにおける亜鉛恒常性の意義が分子レベルで明らかになりつつある。本総説では骨軟骨代謝を制御する亜鉛イオンの役割に焦点をあてて、「亜鉛トランスポーターが輸送する亜鉛イオンは選択的に細胞機能を制御する」という新しい概念"亜鉛シグナル機軸"について議論する。(著者抄録), (株)メディカルレビュー社, 日本語

亜鉛シグナルと免疫
山崎 哲, 北條 慎太郎, 深田 俊幸, 西田 圭吾, 内分泌・糖尿病・代謝内科, 34, 3, 260, 268, 2012年03月, ［査読有り］
(有)科学評論社, 日本語

亜鉛トランスポーター SLC39A14/ZIP14 による全身成長の制御
北條 慎太郎, 深田 俊幸, Biomedical Research on Trace Elements, 23, 1, 6, 13, 2012年04月, ［査読有り］
亜鉛トランスポーター、特にSLC39A14/ZIP14の機能を中心に、哺乳類の全身成長における亜鉛ホメオスタシスの重要性について概説した。Zip-14ノックアウトマウスは全身成長障害と骨軟骨代謝異常を呈する。ZIP14はGタンパク質共役型受容体(GPCR)シグナル伝達を介して軟骨細胞の分化、成長ホルモンの産生と分泌、絶食時の糖新生反応を制御する。ZIP14は全身成長とエネルギー代謝をコントロールするGPCRシグナル伝達機構の新規制御因子である。, 日本微量元素学会, 日本語

全身成長とGPCRシグナル伝達を制御する亜鉛トランスポーターZip14　　　　　　　　　　　　　　　
深田 俊幸, 北條 慎太郎, 下田 信治, 古関 明彦, 平野 俊夫, 日本生化学会大会プログラム・講演要旨集, 84回, 1S16p, 6, 2011年09月
(公社)日本生化学会, 日本語

亜鉛生物学の基礎医学と臨床医学における新展開 亜鉛トランスポーターZip14 全身成長とGPCRシグナル伝達への関与
深田 俊幸, 北條 慎太郎, 下田 信治, 大橋 若菜, 賓 範浩, 古関 明彦, 平野 俊夫, Biomedical Research on Trace Elements, 22, 2, 79, 79, 2011年06月, ［査読有り］
日本微量元素学会, 日本語

【樹状細胞による免疫制御と臨床応用 T細胞制御機構の理解から、樹状細胞療法の開発、自己免疫疾患・感染症の病態解明とその治療まで】樹状細胞の生物学と生理学(分化・サブセット活性化・動態) 樹状細胞による抗原提示の制御機構
北條 慎太郎, 村上 正晃, 実験医学, 26, 20, 3158, 3168, 2008年12月, ［査読有り］
抗原提示とは、樹状細胞をはじめとする抗原提示細胞が細胞内で内在性あるいは外来性抗原を分解し、その抗原ペプチドをT細胞に提示する機構である。ペプチドの提示にはMHCが必要であり、一般的に内在性抗原由来のペプチドはMHCクラスI(MHC I)、外来性抗原抗原由来のペプチドはMHCクラスII(MHC II)によってCD8+T細胞あるいはCD4+T細胞に提示される。免疫寛容あるいは自己免疫応答は主としてMHCを介した樹状細胞とT細胞の相互作用に端を発し、不適当な免疫応答を回避するためにもMHCによる抗原提示機構は厳密に制御されていなければならない。MHCの抗原提示機構の研究はこれまで精力的に行われてきており、将来的に有用な医薬品の開発やワクチン製造に繋がる期待からもこれからますます活発になっていく分野であると言える。事実、近年ではERAAPなどの抗原ペプチドトリミングやその他抗原分解に携わる酵素が同定され、また内在性抗原の提示に限局していたMHC I抗原提示機構においても、従来の古典的経路の概念に当てはまらない複数の新しい外来性抗原のクロスプレゼンテーション経路が発見され脚光を浴びている。本稿では抗原提示の制御機構について最近の知見を含めて概説するとともに、これまでにわれわれが独自に得た抗原提示制御機構、(1)TRIF-GEFH1-RhoBシグナルによるMHC II輸送の制御機構、(2)亜鉛によるMHC II輸送の制御機構、(3)IL-6による樹状細胞成熟化制御についての知見を紹介する。(著者抄録), (株)羊土社, 日本語

亜鉛トランスポーターSlc39a13/Zip13の結合組織における機能解析　　　　　　　　　　　　　　　
深田 俊幸, 古市 達哉, 下田 信治, 美島 健二, 東山 浩之, 伊平 弥生, 朝田 芳信, 北村 浩, 山崎 哲, 北條 慎太郎, 中山 学, 小原 収, 古関 明彦, 池川 志郎, 平野 俊夫, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 81回・31回, 2T26, 6, 2008年11月
(公社)日本生化学会, 日本語

基礎医学から 免疫機構における亜鉛の役割
深田 俊幸, 山崎 哲, 北條 慎太郎, 西田 圭吾, 村上 正晃, 平野 俊夫, 日本医事新報, 4343, 63, 69, 2007年07月, ［査読有り］
(株)日本医事新報社, 日本語

肝細胞がん患者血清中の抗NeuGc抗体活性の測定　　　　　　　　　　　　　　　
甲田 徹三, 北條 慎太郎, 青笹 正義, 日本癌学会総会記事, 61回, 401, 402, 2002年10月
(一社)日本癌学会, 日本語

Zinc Signals in Cellular Functions and Disorders　　　　　　　　　　　　　　　
Fukada T, Hojyo S, Bin B-H, Zinc signal in growth control and bone disease
Springer, Tokyo, 2014年, ［分担執筆］

亜鉛の機能と健康 : 新たにわかった多彩な機能
深田俊幸, 北條慎太郎, 亜鉛シグナルによる成長と骨代謝制御
建帛社, 2013年05月, 9784767961712, vi, 239p, 図版 [2] p, 日本語, ［分担執筆］

炎症病態誘導における自己免疫疾患関連遺伝子C8orf13の役割　　　　　　　　　　　　　　　
北條慎太郎, 下山修平, 田中勇希, 渥美達也, 上村大輔, 村上正晃
第54回北海道病理談話会:第101回北海道医学大会病理分科会, 2021年09月18日, 日本語, 口頭発表（一般）

新規COVID-19マウスモデルを用いた疾患重症化の分子機構解明の試み　　　　　　　　　　　　　　　
北條慎太郎, 長谷部理絵, 田中くみ子, 田中勇希, 内田萌菜, 村上正晃
一般社団法人量子生命科学第3回大会, 2021年09月16日, 日本語, 口頭発表（一般）

ストレス依存性SARS-CoV-2感染マウスモデルを用いたCOVID-19病態機序の解明　　　　　　　　　　　　　　　
北條慎太郎, 田中くみ子, 田中勇希, 長谷部理絵, 内田萌菜, 村上正晃
第42回日本炎症・再生医学会 (Web開催), 2021年07月07日, 口頭発表（招待・特別）
2021年07月07日 - 2021年07月08日, ［招待講演］

C8orf13によるIL-6アンプを介した病態誘導機構　　　　　　　　　　　　　　　
北條慎太郎, 下山修平, 田中勇希, 渥美達也, 上村大輔, 村上正晃, 自己免疫疾患関連遺伝子
第85回日本インターフェロン・サイトカイン学会学術集会 (Web開催), 2021年05月21日, ポスター発表
2021年05月21日 - 2021年05月22日

中枢神経系特異的な活性化モノサイトの長期生存は神経炎症性疾患の再発に必須である。　　　　　　　　　　　　　　　
北條慎太郎, 高橋伸彦, 田中勇希, 村上正晃
一般社団法人量子生命科学第2回大会 (Web開催), 2020年12月23日, 口頭発表（一般）
2020年12月23日 - 2020年12月24日

自己免疫疾患関連遺伝子Xによる非免疫細胞での炎症誘導機構　　　　　　　　　　　　　　　
北條慎太郎, 下山修平, 田中勇希, 渥美達也, 村上正晃
第６回北海道大学部局横断シンポジウム (Web開催), 2020年10月19日, ポスター発表

Antigen priming of XCR1+ dendritic cells guides the differentiation of resting memory T helper cells　　　　　　　　　　　　　　　
Shintaro Hojyo
Department of Microbiology, Infectious Diseases and Immunology, Charité Universitätsmedizin Berlin, Germany, 2019年12月10日, 英語, 公開講演，セミナー，チュートリアル，講習，講義等
［招待講演］

B cells influence on an environmental cue for IL-2-dependent generation of resting memory T helper cells.　　　　　　　　　　　　　　　
Hojyo S, Sarkander J, Wu T.-Y, Mursell M, Radbruch A, Löhning M, Tokoyoda K
47th Annual Meeting of the German Society for Immunology (DGfI), 英語, ポスター発表
2017年09月12日 - 2017年09月15日

B細胞は骨髄におけるメモリーCD4 T細胞の分化を抑制する　　　　　　　　　　　　　　　
北條慎太郎
2016年10月27日, 日本語, 公開講演，セミナー，チュートリアル，講習，講義等
［招待講演］

B cells suppress the establishment of resting memory CD4 T cells in the bone marrow.　　　　　　　　　　　　　　　
Hojyo S, Sarkander J, Radbruch A, Löhning M, Tokoyoda K
46th Annual Meeting of the German Society for Immunology (DGfI), 英語, ポスター発表
2016年09月27日 - 2016年09月30日

T follicular helper cell-independent generation of bone marrow-resident resting memory T helper cells.　　　　　　　　　　　　　　　
Hojyo S., Sarkander J., Tokoyoda K.
4th European Congress of Immunology (ECI), 英語, 口頭発表（一般）
2015年09月06日 - 2015年09月09日

ノックアウトマウスから明らかとなった亜鉛トランスポーターZIP14による骨量制御メカニズム　　　　　　　　　　　　　　　
佐々木 俊, 北條 慎太郎, 深田 俊幸, 古市 達哉
日本獣医学会学術集会講演要旨集, 2014年08月, (公社)日本獣医学会, 日本語
2014年08月 - 2014年08月

亜鉛トランスポーター SLC39A10/ZIP10は、B細胞受容体シグナル伝達を介した成熟B細胞の維持と抗体産生能を制御する。　　　　　　　　　　　　　　　
北條慎太郎, 宮井智浩, 平野俊夫, 深田俊幸
メタロバイオサイエンス研究会2013, 日本語, 口頭発表（一般）
2013年09月26日 - 2013年09月27日

亜鉛トランスポーター SLC39A10/ZIP10は、B細胞受容体シグナル伝達を介した成熟B細胞の恒常性維持と体液性免疫応答を制御する。　　　　　　　　　　　　　　　
北條慎太郎, 深田俊幸, 古関明彦, 平野俊夫
第86回 日本生化学会大会, 日本語, 口頭発表（一般）
2013年09月11日 - 2013年09月13日

亜鉛トランスポーター欠損マウスを用いた亜鉛による骨量制御機構の研究　　　　　　　　　　　　　　　
古市 達哉, 佐々木 俊, 市村 鋭, 北條 慎太郎, 深田 俊幸
日本獣医学会学術集会講演要旨集, 2013年08月, (公社)日本獣医学会, 日本語
2013年08月 - 2013年08月

亜鉛トランスポーター SLC39A10/ZIP10は、B細胞受容体シグナル伝達を介した成熟B細胞の恒常性維持と体液性免疫応答を制御する。　　　　　　　　　　　　　　　
北條慎太郎, 深田俊幸, 下田信治, 大橋若菜, 賓範浩, 古関明彦, 平野俊夫
第8回トランスポーター研究会年会（JTRA2013）, ポスター発表
2013年06月15日 - 2013年06月16日

The Zinc Transporter SLC39A10/ZIP10 Controls B cell Receptor Signaling for Mature B cell Maintenance and Humoral Immune Response　　　　　　　　　　　　　　　
Deutsches Rheuma-Forschungszentrum, Berlin, Germany, 2013年05月15日, 英語, 公開講演，セミナー，チュートリアル，講習，講義等
［招待講演］

The zinc transporter SLC39A14/ZIP14 controls G-Protein coupled receptor-mediated signaling required for systemic growth.　　　　　　　　　　　　　　　
Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin B-H, Koseki H, Hirano T
International society for Zinc Biology 2012 meeting, 英語, ポスター発表
2012年01月15日 - 2012年01月19日

亜鉛トランスポーター SLC39A14/ZIP14は、全身成長に必要なG蛋白共役型受容体シグナル伝達を制御する。　　　　　　　　　　　　　　　
Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin B-H, Koseki H, Hirano T
第34回日本分子生物学会年会, 日本語, 口頭発表（一般）
2011年12月13日 - 2011年12月16日

全身成長とGPCRシグナル伝達を制御する亜鉛トランスポーターZip14　　　　　　　　　　　　　　　
深田 俊幸, 北條 慎太郎, 下田 信治, 古関 明彦, 平野 俊夫
日本生化学会大会プログラム・講演要旨集, 2011年09月, (公社)日本生化学会, 日本語
2011年09月 - 2011年09月

亜鉛トランスポーター SLC39A14/ZIP14はG蛋白質共役型受容体(GPCR)を介した内分泌系シグナルを制御する。　　　　　　　　　　　　　　　
北條慎太郎, 深田俊幸, 下田信治, 大橋若菜, 賓範浩, 古関明彦, 平野俊夫
第6回トランスポーター研究会年会（JTRA2011), 日本語, ポスター発表
2011年06月11日 - 2011年06月12日

亜鉛トランスポーター Slc39a14/Zip14はG蛋白質共役型受容体 (GPCR)を介した内分泌シグナルを制御する。　　　　　　　　　　　　　　　
北條慎太郎, 深田俊幸, 下田信治, 大橋若菜, 賓範浩, 古関明彦, 平野俊夫
第33回日本分子生物学会年会 第83回日本生化学会大会合同大会 (Biochemistry and Molecular Biology BMB2010), 日本語, ポスター発表
2010年12月07日 - 2010年12月10日

亜鉛トランスポーター Slc39a14/Zip14はG蛋白質共役型受容体シグナル伝達を制御する。　　　　　　　　　　　　　　　
Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin B-H, Koseki H, Hirano T
第60回藤原セミナー: Zinc Signaling and Cellular Functions, 英語, ポスター発表
2010年10月29日 - 2010年10月31日

樹状細胞におけるIL-6-細胞内亜鉛ホメオスタシスを介したMHCIIおよび共刺激分子の発現制御の可能性　　　　　　　　　　　　　　　
Hojyo S, Fukada T, Hayashi E, Kitamura H, Murakami M, Hirano T
第36回 日本免疫学会総会 学術集会, 日本語, ポスター発表
2006年12月11日 - 2006年12月13日

生命薬学特論　　　　　　　　　　　　　　　
北海道大学
2021年06月 - 2021年07月

生物学I　　　　　　　　　　　　　　　
北海道大学
2021年06月 - 2021年07月

Basic Medical Biology　　　　　　　　　　　　　　　
北海道大学
2020年10月 - 2020年10月

生命薬学特論　　　　　　　　　　　　　　　
北海道大学
2020年07月 - 2020年08月

生物学I　　　　　　　　　　　　　　　
北海道大学
2020年07月 - 2020年08月

1st Lecture Series on Chronic Inflammation　　　　　　　　　　　　　　　
Deutsches Rheuma-Forschungszentrum, Berlin, Germany
2019年01月

2020年 - 現在
日本免疫学会　　　　　　　　　　　　　　　

2020年
量子生命科学会　　　　　　　　　　　　　　　

自己免疫疾患の再発に必須の中枢神経系モノサイトの長期生存能獲得分子機構の解明
科学研究費助成事業 基盤研究(C)
2021年04月01日 - 2024年03月31日
北條 慎太郎
多発性硬化症 (MS)は自己反応性CD4 T細胞が関与する自己免疫疾患であり、しばしば痛みを伴い、再発と寛解の繰り返しにより症状が悪化する。しかしながら、再発誘導の分子機序は不明であった。我々は以前に、MS動物モデルである移入実験的自己免疫性脳脊髄炎(EAE)モデルを用いて、病態寛解期の痛み刺激が感覚神経から交感神経への興奮伝達を介して、EAE初発炎症時に末梢組織から移行し寛解期を通じて中枢神経系 (CNS)に長期定着するモノサイトを活性化することによって病態を再発させることを報告した。本研究では、CNSモノサイトを細胞標的とした創薬を念頭に、当該細胞の長期生存機構を分子レベルで解明し、疾患再発の新しい予防戦略を提示することを目的とする。具体的には、(1) CNSモノサイトの起源と長期生存能の獲得機構の解析、(2) 寛解期におけるCNS モノサイト特異的な表面マーカーの同定と機能解析、(3) CNSモノサイトと血管内皮細胞の特異的な相互作用の解析を行う。
日本学術振興会, 基盤研究(C), 北海道大学, 21K07075

ストレス依存性突然死を誘導する新規COVID-19モデルマウスを用いたCOVID-19重症化に対する創薬標的の同定と非臨床試験　　　　　　　　　　　　　　　
GSKジャパン研究助成
2021年 - 2023年
北條慎太郎
グラクソ・スミスクライン(GSK)株式会社, D. ウイルス性疾患, 北海道大学遺伝子病制御研究所分子神経免疫学分野, 研究代表者

ストレス依存性微小炎症による進行型多発性硬化症の発症機序の解明　　　　　　　　　　　　　　　
医学系研究助成（精神・神経・脳領域）
2021年 - 2023年
北條慎太郎
公益財団法人 武田科学振興財団, 医学系, 北海道大学遺伝子病制御研究所分子神経免疫学分野, 研究代表者

亜鉛トランスポーター ZIP10によるBCRシグナル制御機構の解明
科学研究費助成事業 若手研究(B)
2013年04月01日 - 2014年03月31日
北條 慎太郎
申請者は、亜鉛トランスポーターが輸送する亜鉛イオンがシグナル因子として機能し（亜鉛シグナル）、骨軟骨代謝や免疫応答に深く関わることを明らかにしてきた。亜鉛の欠乏症は重篤な免疫機能の低下を引き起こすことが知られているが、亜鉛や亜鉛トランスポーターがどのように免疫系を制御しているのか、その分子機序は明らかにされていない。本申請研究は、免疫系の一つの柱である抗体産生に関わるB細胞において高い発現を示す亜鉛トランスポーター ZIP10に注目し、B細胞特異的にZIP10を欠損したマウスを構築することによってその機能を解析した。ZIP10欠損マウスでは末梢の成熟B細胞の減少が認められ、それが関与する抗原特異的な抗体産生能が減弱していた。また、ZIP10を欠損したB細胞の寿命は野生型と比較して短く、この表現型はB細胞内因性の異常に起因していることが判明した。
成熟B細胞の生存や抗体産生能はB細胞受容体(BCR)シグナルによって制御されていることが知られている。ZIP10欠損B細胞では、BCR刺激依存的な細胞増殖能の低下が認められ、BCRシグナル伝達の異常が確認された。興味深いことに、予想に反して、ZIP10欠損B細胞ではBCRシグナル伝達の中心的な役割を果たすSrcファミリーキナーゼ LYNの活性化がBCR刺激後に亢進しており、この原因の一つとしてLYNの制御因子であるCD45の脱リン酸化活性が減弱していることがわかった。すなわち、今回得られた結果は、ZIP10がBCRシグナル伝達における新規のレギュレーターであり、CD45の活性を介してシグナル強度を調節することによって、B細胞の機能を制御していることを明示するものである (論文投稿準備中)。本研究は、第八回 トランスポーター研究会年会 優秀発表賞 および 第86回日本生化学会大会 鈴木紘一メモリアル賞 の表彰を受けた。
日本学術振興会, 若手研究(B), 独立行政法人理化学研究所, 25860371