田中　宏樹 (タナカ　ヒロキ)

遺伝子病制御研究所　病因研究部門特任講師
Last Updated :2026/03/05

■研究者基本情報

学位

  • 博士(理学), 大阪大学, 2010年09月

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■研究活動情報

論文

  • Neural signaling in immunology: the gateway reflex.
    Rie Hasebe, Hiroki Tanaka, Takeshi Yamasaki, Kaoru Murakami, Masaaki Murakami
    International immunology, 37, 7, 369, 377, 2025年06月17日, ［国際誌］
    英語, 研究論文（学術雑誌）, Neural signaling regulates various reactions in our body including immune responses. Neuromodulation of this signaling using artificial neural activation and/or suppression is a potential treatment for diseases and disorders. We here review neural signaling regulating the immune system, with a special focus on the gateway reflex. The gateway reflex is a novel neuro-immune crosstalk mechanism that regulates tissue-specific inflammatory diseases. We have discovered six gateway reflexes so far; all are induced by environmental or artificial stimulations including gravity, electrical stimulation, pain sensation, stress, light, and inflammation in joints. In the presence of increased autoreactive T cells in the blood, such stimulation activates specific neural signaling to release noradrenaline (NA) from the nerve endings at specific blood vessels in the central nervous system. NA activates the interleukin-6 (IL-6) amplifier, which leads to the hyper-activation of nuclear factor-kappa B (NF-κB) in non-immune cells, resulting in the formation of a gateway. This gateway allows autoreactive T cells and other immune cells to accumulate in the target tissue to induce inflammatory diseases. In gateway reflexes induced by stress or remote inflammation, adenosine triphosphate (ATP) secreted from inflammation sites activates specific neural pathways, resulting in organ dysfunction and inflammation in other tissues, suggesting that the gateway reflex regulates tissue-specific inflammatory diseases by bidirectional crosstalk between the neural and immune systems. We also discuss other cases of neural signaling including the inflammatory reflex.
  • 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, ［査読有り］
    研究論文（学術雑誌）
  • Gateway reflexes describe novel neuro-immune communications that establish immune cell gateways at specific vessels.
    Hiroki Tanaka, Rie Hasebe, Kaoru Murakami, Toshiki Sugawara, Takeshi Yamasaki, Masaaki Murakami
    Bioelectronic medicine, 9, 1, 24, 24, 2023年11月08日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Neuroinflammation is an important biological process induced by complex interactions between immune cells and neuronal cells in the central nervous system (CNS). Recent research on the bidirectional communication between neuronal and immunological systems has provided evidence for how immune and inflammatory processes are regulated by nerve activation. One example is the gateway reflex, in which immune cells bypass the blood brain barrier and infiltrate the CNS to cause neuroinflammation. We have found several modes of the gateway reflex in mouse models, in which gateways for immune cells are established at specific blood vessels in the spinal cords and brain in experimental autoimmune encephalomyelitis and systemic lupus erythematosus models, at retinal blood vessels in an experimental autoimmune uveitis model, and the ankle joints in an inflammatory arthritis model. Several environmental stimulations, including physical and psychological stresses, activate neurological pathways that alter immunological responses via the gateway reflex, thus contributing to the development/suppression of autoimmune diseases. In the manuscript, we describe the discovery of the gateway reflex and recent insights on how they regulate disease development. We hypothesize that artificial manipulation of specific neural pathways can establish and/or close the gateways to control the development of autoimmune diseases.
  • Breaking self-regulation of Regnase-1 promotes its own protein expression.
    Kitiya Piboonprai, Arthur Millius, Mayuko Shimoda, Hiroki Tanaka, Shizuo Akira, Kazuhiko Maeda
    Genes to cells : devoted to molecular & cellular mechanisms, 28, 5, 383, 389, 2023年02月23日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, The RNA-binding protein (RBP) Regnase-1 is an endonuclease that regulates immune responses by modulating target mRNA stability. Regnase-1 degrades a group of inflammation-associated mRNAs, which contributes to a balanced immune response and helps prevent autoimmune diseases. Regnase-1 also cleaves its own mRNA by binding stem-loop (SL) RNA structures in its 3'UTR. To understand how this autoregulation is important for immune responses, we generated mice with a 2-bp genome deletion in the target SL of the Regnase-1 3'-untranslated region (3'UTR). Deletion of these nucleotides inhibited SL formation and limited Regnase-1-mediated mRNA degradation. Mutant mice had normal hematopoietic cell differentiation. Biochemically, mutation of the 3'UTR SL increased Regnase-1 mRNA stability and enhanced both Regnase-1 mRNA and protein levels in mouse embryonic fibroblasts (MEFs). The expression of Il6, a Regnase-1 target gene, was constitutively suppressed at steady-state in mutant MEFs. Additionally, Regnase-1 protein expression in mutant MEFs was significantly elevated compared to that in wild-type MEFs at steady state and upon proinflammatory cytokine stimulation. These data suggest a negative feedback mechanism for Regnase-1 expression and represent a unique mouse model to probe Regnase-1 overexpression in vivo.
  • Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease.
    Takahiro Kawasaki, Fuminori Sugihara, Kiyoharu Fukushima, Takanori Matsuki, Hiroshi Nabeshima, Tomohisa Machida, Yuichi Mitsui, Saki Fujimura, Rio Sagawa, Lee Gaheun, Kanako Kuniyoshi, Hiroki Tanaka, Masashi Narazaki, Atsushi Kumanogoh, Shizuo Akira, Takashi Satoh
    Proceedings of the National Academy of Sciences of the United States of America, 118, 26, 2021年06月29日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout (Fchsd1 -/-) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1 -/- mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1 -/- mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive transcription factor, following H2O2 stimulation. Conversely, Fchsd1 overexpression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.
  • Rhodobacter azotoformans LPS (RAP99-LPS) Is a TLR4 Agonist That Inhibits Lung Metastasis and Enhances TLR3-Mediated Chemokine Expression.
    Kaoru Murakami, Daisuke Kamimura, Rie Hasebe, Mona Uchida, Nobuya Abe, Reiji Yamamoto, Jing-Jing Jiang, Yasuhiro Hidaka, Yuko Nakanishi, Shuzo Fujita, Yuki Toda, Nobuhiro Toda, Hiroki Tanaka, Shizuo Akira, Yuki Tanaka, Masaaki Murakami
    Frontiers in immunology, 12, 675909, 675909, 2021年, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, The lipopolysaccharides (LPSs) of Rhodobacter are reported to be TLR4 antagonists. Accordingly, the extract of Rhodobacter azotoformans (RAP99) is used as a health supplement for humans and animals in Japan to regulate immune responses in vivo. We previously analyzed the LPS structure of RAP99 (RAP99-LPS) and found it is different from that of E. coli-LPS but similar to lipid A from Rhodobacter sphaeroides (RSLA), a known antagonist of TLR4, with both having three C14 fatty acyl groups, two C10 fatty acyl groups, and two phosphates. Here we show that RAP99-LPS has an immune stimulatory activity and acts as a TLR4 agonist. Pretreatment of RAP99-LPS suppressed E. coli-LPS-mediated weight loss, suggesting it is an antagonist against E. coli-LPS like other LPS isolated from Rhodobacter. However, injections of RAP99-LPS caused splenomegaly and increased immune cell numbers in C57BL/6 mice but not in C3H/HeJ mice, suggesting that RAP99-LPS stimulates immune cells via TLR4. Consistently, RAP99-LPS suppressed the lung metastasis of B16F1 tumor cells and enhanced the expression of TLR3-mediated chemokines. These results suggest that RAP99-LPS is a TLR4 agonist that enhances the activation status of the immune system to promote anti-viral and anti-tumor activity in vivo.
  • Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages.
    Kenta Maruyama, Hiroyasu Kidoya, Naoki Takemura, Erika Sugisawa, Osamu Takeuchi, Takeshi Kondo, Mohammed Mansour Abbas Eid, Hiroki Tanaka, Mikaël M Martino, Nobuyuki Takakura, Yasunori Takayama, Shizuo Akira, Alexis Vandenbon, Yutaro Kumagai
    Cell reports, 32, 2, 107906, 107906, 2020年07月14日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Zinc finger protein St18 was initially reported as candidate tumor suppressor gene, and also suggested that fibroblast St18 positively regulates NF-κB activation. Despite the pleiotropic functions of St18, little is known about its roles in macrophages. Here, we report that myeloid St18 is a potent inhibitor of VEGF-A. Mice lacking St18 in myeloid lineages exhibit increased retinal vasculature with enhanced serum VEGF-A concentrations. Despite the normal activation of NF-κB target genes, these mice are highly susceptible to LPS-induced shock, polymicrobial sepsis, and experimental colitis, accompanied by enhanced vascular and intestinal leakage. Pharmacological inhibition of VEGF signaling rescued the high mortality rate of myeloid-specific St18-deficient mice in response to inflammation. Mechanistically, St18 directly binds to Sp1 and attenuates its activity, leading to the suppression of Sp1 target gene VEGF-A. Using mouse genetic and pharmacological models, we reveal myeloid St18 as a critical septic death protector.
  • Regnase-1 degradation is crucial for IL-33- and IL-25-mediated ILC2 activation.
    Kazufumi Matsushita, Hiroki Tanaka, Koubun Yasuda, Takumi Adachi, Ayumi Fukuoka, Shoko Akasaki, Atsuhide Koida, Etsushi Kuroda, Shizuo Akira, Tomohiro Yoshimoto
    JCI insight, 5, 4, 2020年02月27日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Group 2 innate lymphoid cells (ILC2s) are a critical innate source of type 2 cytokines in allergic inflammation. Although ILC2s are recognized as a critical cell population in the allergic inflammation, the regulatory mechanism(s) of ILC2s are less well understood. Here, we show that Regnase-1, an immune regulatory RNAse that degrades inflammatory mRNAs, negatively regulates ILC2 function and that IκB kinase (IKK) complex-mediated Regnase-1 degradation is essential for IL-33- and IL-25-induced ILC2 activation. ILC2s from Regnase-1AA/AA mice expressing a Regnase-1 S435A/S439A mutant resistant to IKK complex-mediated degradation accumulated Regnase-1 protein in response to IL-33 and IL-25. IL-33- and IL-25-stimulated Regnase-1AA/AA ILC2s showed reduced cell proliferation and type 2 cytokine (IL-5, IL-9, and IL-13) production and increased cell death. In addition, Il2ra and Il1rl1, but not Il5, Il9, or Il13, mRNAs were destabilized in IL-33-stimulated Regnase-1AA/AA ILC2s. In vivo, Regnase-1AA/AA mice showed attenuated acute type 2 pulmonary inflammation induced by the instillation of IL-33, IL-25, or papain. Furthermore, the expulsion of Nippostrongylus brasiliensis was significantly delayed in Regnase-1AA/AA mice. These results demonstrate that IKK complex-mediated Regnase-1 degradation is essential for ILC2-mediated type 2 responses both in vitro and in vivo. Therefore, controlling Regnase-1 degradation is a potential therapeutic target for ILC2-contributed allergic disorders.
  • Regnase-１蛋白質のリン酸化に伴う小胞体からの脱離はインターロイキン17による炎症応答に必須である
    Hiroki Tanaka, Yasunobu Arima, Daisuke Kamimura, Yuki Tanaka, Noriyuki Takahashi, Takuya Uehata, Kazuhiko Maeda, Takashi Satoh, Masaaki Murakami, Shizuo Akira
    Journal of Experimental Medicine, 216, 6, 1431, 1449, Rockefeller University Press, 2019年06月03日, ［査読有り］, ［筆頭著者］, ［国際誌］
    英語, 研究論文（学術雑誌）, Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi–dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17–induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD) were resistant to the IL-17–mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17–mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.
  • Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism.
    Yasuharu Nagahama, Mayuko Shimoda, Guoliang Mao, Shailendra Kumar Singh, Yuuki Kozakai, Xin Sun, Daisuke Motooka, Shota Nakamura, Hiroki Tanaka, Takashi Satoh, Kazuhiko Maeda, Shizuo Akira
    Proceedings of the National Academy of Sciences of the United States of America, 115, 43, 11036, 11041, 2018年10月23日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Damage to intestinal epithelial cell (IEC) layers during intestinal inflammation is associated with inflammatory bowel disease. Here we show that the endoribonuclease Regnase-1 controls colon epithelial regeneration by regulating protein kinase mTOR (the mechanistic target of rapamycin kinase) and purine metabolism. During dextran sulfate sodium-induced intestinal epithelial injury and acute colitis, Regnase-1∆IEC mice, which lack Regnase-1 specifically in the intestinal epithelium, were resistant to body weight loss, maintained an intact intestinal barrier, and showed increased cell proliferation and decreased epithelial apoptosis. Chronic colitis and tumor progression were also attenuated in Regnase-1∆IEC mice. Regnase-1 predominantly regulates mTORC1 signaling. Metabolic analysis revealed that Regnase-1 participates in purine metabolism and energy metabolism during inflammation. Furthermore, increased expression of ectonucleotidases contributed to the resolution of acute inflammation in Regnase-1∆IEC mice. These findings provide evidence that Regnase-1 deficiency has beneficial effects on the prevention and/or blocking of intestinal inflammatory disorders.
  • The ATP Transporter VNUT Mediates Induction of Dectin-1-Triggered Candida Nociception.
    Kenta Maruyama, Yasunori Takayama, Erika Sugisawa, Yu Yamanoi, Takashi Yokawa, Takeshi Kondo, Ken-Ichi Ishibashi, Bikash Ranjan Sahoo, Naoki Takemura, Yuki Mori, Hisashi Kanemaru, Yutaro Kumagai, Mikaël M Martino, Yoshichika Yoshioka, Hisao Nishijo, Hiroki Tanaka, Atsushi Sasaki, Naohito Ohno, Yoichiro Iwakura, Yoshinori Moriyama, Masatoshi Nomura, Shizuo Akira, Makoto Tominaga
    iScience, 6, 306, 318, 2018年08月31日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Candida albicans infection can cause skin, vulvar, or oral pain. Despite the obvious algesic activity of C. albicans, the molecular mechanisms of fungal nociception remain largely unknown. Here we show that the C. albicans-specific signaling pathway led to severe mechanical allodynia. We discovered that C. albicans-derived β-glucan stimulated nociceptors depending on Dectin-1, and two pathways in inflammatory pain. The major pathway operates via the Dectin-1-mediated ATP-P2X3/P2X2/3 axis through intercellular relationships between keratinocytes and primary sensory neurons, which depends on the ATP transporter vesicular nucleotide transporter (VNUT). The other pathway operates via the Dectin-1-mediated PLC-TRPV1/TRPA1 axis in primary sensory neurons. Intriguingly, C. albicans-derived β-glucan has the ability to enhance histamine-independent pruritus, and VNUT inhibitor clodronate can be used to treat unpleasant feelings induced by β-glucan. Collectively, this is the first report to indicate that Dectin-1 and VNUT mediated innate sensory mechanisms that detect fungal infection.
  • BATF2 activates DUSP2 gene expression and up-regulates NF-κB activity via phospho-STAT3 dephosphorylation.
    Hisashi Kanemaru, Fumihiro Yamane, Hiroki Tanaka, Kazuhiko Maeda, Takashi Satoh, Shizuo Akira
    International immunology, 30, 6, 255, 265, 2018年05月24日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Growing evidence has revealed that the transcription factor basic leucine zipper transcription factor ATF-like 2 (BATF2) has unique transcriptional activities, including regulating cytokines via TLR signals in macrophages, which affect mortality due to infection and cancer. On the basis of genome-wide analyses using the chromatin immunoprecipitation-sequencing technique, we found that dual-specificity phosphatase 2 (Dusp2) had a significantly lower acetyl-histone status in Batf2-/- bone marrow-derived macrophages (BMDMs) compared with wild-type (WT) BMDMs. The phosphatase DUSP2 has been reported to play a critical role in inflammatory responses. Therefore, we evaluated the BATF2 transcriptional activities on the Dusp2 promoter. We found that the DUSP2 and IL-12 p40 expression levels were significantly lower in Batf2-/- BMDMs than in WT controls following their stimulation with TLR7 ligands. Further in vitro studies revealed that phospho-STAT3 was up-regulated and NF-κB p50/p65 were down-regulated in Batf2-/- BMDMs compared with their levels in WT controls. Additionally, Th1 immunity was impaired in Batf2-/- mice following their stimulation with TLR7 ligands. We also found that BATF2 interacts with NF-κB p65 and promotes DUSP2 expression through the NF-κB-binding site in the Dusp2 promoter at -203 to -121. Collectively, our findings suggest that BATF2 activates DUSP2 gene expression and up-regulates NF-κB activity via phospho-STAT3 dephosphorylation.
  • Schlafen-8 is essential for lymphatic endothelial cell activation in experimental autoimmune encephalomyelitis
    Katsuhiro Nakagawa, Takanori Matsuki, Liang Zhao, Kanako Kuniyoshi, Hiroki Tanaka, Isao Ebina, Kenta J. Yoshida, Hiroshi Nabeshima, Kiyoharu Fukushima, Hisashi Kanemaru, Fumihiro Yamane, Takahiro Kawasaki, Tomohisa Machida, Hisamichi Naito, Nobuyuki Takakura, Takashi Satoh, Shizuo Akira
    International Immunology, 30, 2, 69, 78, Oxford University Press, 2018年03月08日, ［査読有り］
    英語, 研究論文（学術雑誌）
  • Antitumor effect of Batf2 through IL-12 p40 up-regulation in tumor-associated macrophages
    Hisashi Kanemaru, Fumihiro Yamane, Kiyoharu Fukushima, Takanori Matsuki, Takahiro Kawasaki, Isao Ebina, Kanako Kuniyoshi, Hiroki Tanaka, Kenta Maruyama, Kazuhiko Maeda, Takashi Satoh, Shizuo Akira
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114, 35, E7331, E7340, 2017年08月, ［査読有り］
    英語, 研究論文（学術雑誌）
  • Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis
    Kenta Maruyama, Yasunori Takayama, Takeshi Kondo, Ken-ichi Ishibashi, Bikash Ranjan Sahoo, Hisashi Kanemaru, Yutaro Kumagai, Mikael M. Martino, Hiroki Tanaka, Naohito Ohno, Yoichiro Iwakura, Naoki Takemura, Makoto Tominaga, Shizuo Akira
    CELL REPORTS, 19, 13, 2730, 2742, 2017年06月, ［査読有り］
    英語, 研究論文（学術雑誌）
  • Poly IC Triggers a Cathepsin D- and IPS-1-Dependent Pathway to Enhance Cytokine Production and Mediate Dendritic Cell Necroptosis
    Jian Zou, Taro Kawai, Tetsuo Tsuchida, Tatsuya Kozaki, Hiroki Tanaka, Kyung-Sue Shin, Himanshu Kumar, Shizuo Akira
    IMMUNITY, 38, 4, 717, 728, 2013年04月, ［査読有り］
    英語, 研究論文（学術雑誌）
  • Higher-Order Architecture of Cell Adhesion Mediated by Polymorphic Synaptic Adhesion Molecules Neurexin and Neuroligin
    Hiroki Tanaka, Naoyuki Miyazaki, Kyoko Matoba, Terukazu Nogi, Kenji Iwasaki, Junichi Takagi
    Cell Reports, 2, 1, 101, 110, Elsevier BV, 2012年07月, ［査読有り］, ［筆頭著者］
    研究論文（学術雑誌）
  • Structural Basis for Variant-Specific Neuroligin-Binding by α-Neurexin
    Hiroki Tanaka, Terukazu Nogi, Norihisa Yasui, Kenji Iwasaki, Junichi Takagi
    PLoS ONE, 6, 4, e19411, e19411, Public Library of Science (PLoS), 2011年04月28日, ［査読有り］, ［筆頭著者］
    研究論文（学術雑誌）

その他活動・業績

共同研究・競争的資金等の研究課題

  • Regnase-1を介したmRNA管理機構の包括的理解
    科学研究費助成事業
    2020年08月31日 - 2025年03月31日
    審良 静男, 前田 和彦, 田中 宏樹, シン シャイレンドラ・クマール, 國吉 佳奈子
    本年度は研究計画に基づき以下の課題に取り組んだ。
    T細胞サブセット特異的Regnase-1欠損マウスの作製と機能解析については、T細胞の活性化から抗体産生B細胞の経路も検討するために、B細胞特異的Cre発現マウスを用いてB細胞特異的Regnase-1欠損マウスを作製し、野生型及び変異マウス由来B細胞の遺伝子発現パターンの比較を通じて、Reganse-1のB細胞特的な標的遺伝子を同定した。NK細胞特異的Reganse-1欠損マウスの機能解析については、シングルセル解析から判明したRegnase-1の標的遺伝子の一つがNK細胞の抗腫瘍活性と強く相関していることを見出した。この遺伝子は抗腫瘍活性に寄与する遺伝子群の転写制御因子であり、Regnase-1は、標的遺伝子の発現制御を通じてNK細胞における抗腫瘍関連遺伝子の転写および発現の制御を行っていることが判明した。ヌクレアーゼ活性阻害変異マウスの機能解析については、このマウスが肺においてGlanuloma様の構造体を形成すること、これが変異マウス由来T細胞の肺組織への浸潤が引き金となって起こることを見出した。またこのマウス由来のT細胞は、Regnase-1遺伝子欠損マウス由来のT細胞と同様にエフェクター・メモリー化が進んでおり、各臓器及び末梢血において長期間生存することが判明した。臓器特異的Regnase-1欠損マウスの作製と解析については、肝細胞特異的Cre発現マウス及び褐色脂肪細胞特異的Cre発現マウスとRegnase-1 floxマウスを交配することで、肝臓及び脂肪組織特異的にRegnase-1を欠損するマウスの作製に成功した。これらのマウスに対して細胞及び組織ストレスを付与するマウスモデル（肝臓：非アルコール性肝障害モデル、脂肪組織：低温ストレスモデル）を適用し、それらの疾患症状の進展を現在評価している。
    日本学術振興会, 基盤研究(S), 大阪大学, 20H05693
  • RNA分解酵素Regnase-1の不活性化を通じた機能制御機構の解明
    科学研究費助成事業
    2020年04月01日 - 2023年03月31日
    田中 宏樹
    本年度は研究計画のうち、以下の計画について実験の実施および結果の評価を行った。
    特定の細胞集団におけるRegnase-1の蛋白質分解メカニズムの解明については、顆粒球においてRegnase-1蛋白質が分解されることを見出したが、これらの蛋白質切断は、細胞を界面活性剤によって溶解した際に、分泌顆粒に含まれる大量のプロテアーゼが細胞質のRegnase-1を分解することによって生じたアーティファクトであることが判明した。
    Regnase-1のリン酸化阻害変異マウスの自己免疫疾患モデルマウスに対する影響の解明について、Regnase-1のΔCTD変異と自己免疫疾患モデルマウスC57BL/6 lprとの交配を行い、それらの交配マウスがリンパ節の肥大やIg産生量を増大させ、自己免疫症状を亢進させることが判明した。Regnase-1のΔCTD変異がlprマウスに与える影響を解明するために、このマウスのリンパ節組織に対してシングルセル解析を行ったところ、特定の免疫細胞集団が強く活性化することが判明した。現在この免疫細胞活性化のメカニズムを詳細に解析し、リンパ節肥大等の免疫応答の増強との関連を調べている。また全身性エリテマトーデス(SLE)のモデルマウスであるMRL/Lpr系統に対して、ゲノム編集技術によってRegnase-1のΔCTD変異を導入した変異マウスの作製を行った。こちらのマウスにおいても全身性の免疫症状や腎臓機能に対する変異の効果を検証している。
    Regnase-1のリン酸化阻害変異マウスのアレルギー疾患モデルマウスに対する影響の解析については、Balb/cバックグラウンドのリン酸化阻害変異マウスを作製し（AA変異、ΔCTD変異）、それらの疾患に対する影響を評価した。その結果、両変異マウスはアレルギー疾患症状を軽減する効果があることが判明した。
    日本学術振興会, 基盤研究(B), 大阪大学, 20H03502
  • Regnase-1によるmRNA管理機構の統合的理解
    科学研究費助成事業
    2020年04月01日 - 2021年03月31日
    審良 静男, 前田 和彦, 田中 宏樹, 國吉 佳奈子
    本研究では、これまで報告されていない組織・細胞種におけるエンドリボヌクレアーゼRegnase-1の役割や、Regnase-1自身の多彩な制御メカニズムを明らかとしていくため、以下のことを推進した。
    1.新規Cre誘導性マウスの導入、CRISPR/Cas9システムによる新規Regnase-1変異マウス作製、アデノ随伴ウイルスを用いた局所移入法、コロニー拡張、ホモ化を図った。
    2.上記新規マウスおよび維持系統マウスから、免疫細胞および非免疫細胞における表現型の解析及びRegnase-1の制御因子探索を進めるため、質量分析、RNA-seq、シングルセル解析、CyTOFマスサイトメトリーを活用した解析プラットフォームの拡充を図った。病態との関係性を検討するため、非コードRNAやRNA修飾経路も含めた多面的な分析を進めた。
    3.Regnase-1との接点を鑑みつつ、mRNA安定性制御の理解に繋がる新規機能分子や制御経路の探索を推進した。候補因子群が直接的あるいは間接的な関与としての位置づけなのか、個別解析と遺伝子欠損マウス作製も含めて検討した。
    日本学術振興会, 基盤研究(A), 大阪大学, 20H00506
  • RNA分解酵素Regnase-1のリン酸化を介した炎症反応制御
    科学研究費助成事業
    2018年04月01日 - 2020年03月31日
    田中 宏樹
    炎症反応は、様々な細胞刺激物質が免疫細胞やその周辺の臓器由来細胞の表面に存在する受容体に結合し、炎症に関与する複数の遺伝子産生のスイッチが「オン」になることによって引き起こされる。本研究課題では、これらの遺伝子の産生の「オン」と「オフ」の切り替えを制御する酵素Regnase-1の役割の解明に取り組んだ。そして、炎症を引き起こす物質の一つであるインターロイキン１７がRegnase-1のリン酸化とこの酵素の不活性化に関与していること、Regnase-1のリン酸化がこの物質の関与する慢性炎症疾患の増悪に関与していることを明らかにし、このリン酸化の抑制が疾患治療の主要な標的になり得ることを示した。
    日本学術振興会, 若手研究, 大阪大学, 18K15189
  • 自然免疫の包括的理解
    科学研究費助成事業
    2015年 - 2019年
    審良 静男, 佐藤 荘, 國吉 佳奈子, 前田 和彦, 田中 宏樹
    自然免疫に重要な役割を果たす分子群の機能を生体レベルで明らかにしていくため、免疫機能に関与する遺伝子欠損マウスの作製と解析を軸とした研究を進めた。特に、代表者らが新たに切り拓いた“mRNA安定性制御機構”及び“疾患特異的マクロファージサブタイプ”の視点から、免疫関連疾患の病態解明や原因究明に繋がる研究を推進し、以下の成果を得た。“mRNA安定性制御機構”では、免疫応答を制御するRNA分解酵素Regnase-1が、炎症応答により誘導されるリン酸化を介して標的遺伝子のmRNA安定性を制御することを明らかにした。また、Regnase-1は炎症応答以外に、腸管上皮細胞においてmTORシグナル経路とプリン代謝に関与する遺伝子のmRNA発現量を制御し、早期炎症収束と再生に関与していることを発見した。“疾患特異的マクロファージサブタイプ”では、SatMと名付けた新たなマクロファージのサブセットが、臓器における線維症の発症や増悪に関わることを発見した。SatMは通常のマクロファージとは異なる分化系譜によって発生し、C/EBPβによって分化が制御されていることを明らかにした。さらに、インターフェロン誘導性転写因子BATF2がマクロファージにおけるTLR7誘導性IL-12産生を調節することを明らかとし、BATF2が癌治療標的となりうることを示した。
    日本学術振興会, 特別推進研究, 大阪大学, 15H05704