先端研究院
プロテオサイエンスセンター
English
更新日：2025/01/13
教授
ﾏｽﾓﾄ　ｼﾞｭﾝﾔ
増本　純也

経歴

  1. 2000/01-2000/03信州大学医学部非常勤研究員
  2. 2000/05-2001/03信州大学医学部非常勤研究員
  3. 2002/01-2004/03ミシガン大学 医学部病理学リサーチ・フェロー
  4. 2004/04-2005/04信州大学 医学部 附属病院臨床検査部医員
  5. 2005/04-2007/03信州大学 医学部病理組織学助手
  6. 2007/04-2007/05信州大学 医学部病理組織学助教
  7. 2007/05-2011/04信州大学 医学部病理組織学講師
  8. 2011/04-2012/01信州大学 大学院 医学系研究科分子病理学講師
  9. 2012/01-2012/01愛媛大学 大学院 医学系研究科ゲノム病理学教授
  10. 2012/02-2013/03愛媛大学プロテオ医学研究センター教授
  11. 2013/04-現在愛媛大学 プロテオサイエンスセンターProteo-Science Center教授

学歴

  1. 富山医科薬科大学1986/041990/03
  2. 信州大学1990/041996/03
  3. 信州大学大学院医学系研究科1996/041999/12

学位

  1. 博士(医学)信州大学

免許・資格

  1. 日本がん治療認定医機構がん治療認定医

研究分野

  1. ライフサイエンス人体病理学リウマチ学
  2. ライフサイエンス膠原病、アレルギー内科学炎症学
  3. その他その他消化管内視鏡学 病態検査学

研究キーワード

  1. IL-1β
  2. ヘリコバクター
  3. 自己炎症性疾患
  4. インフラマソーム
  5. 自然免疫
  6. 病理学
  7. 炎症
  8. 炎症性疾患

共同研究・競争的資金等の研究課題

  1. 自己炎症疾患責任遺伝子変異症例の前向き研究による自己炎症疾患発症トリガーの解明基盤研究(B)競争的資金
  2. トルコと日本の自己炎症疾患症例の血清中インフラマソーム活性化因子の比較調査研究基盤研究(B)競争的資金
  3. トルコと日本の自己炎症疾患発症責任分子複合体を活性化する生体・環境因子の比較調査基盤研究(B)競争的資金
  4. 難病から『インフラマソーム病』を独立させ、分子標的に基いた診断の再編成を加速する挑戦的研究(萌芽)競争的資金
  5. 自己炎症疾患の発作の周期性や炎症の多様性を規定する責任分子調節分子群の包括的同定基盤研究(B)競争的資金
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論文

  1. CANE, a Component of the NLRP3 Inflammasome, Promotes Inflammasome Activation.2024/07/01Kaneko Naoe,Kurata Mie,Yamamoto Toshihiro,Sakamoto Akimasa,Takada Yasutsugu,Kosako Hidetaka,Takeda Hiroyuki,Sawasaki Tatsuya,Masumoto JunyaJournal of immunology (Baltimore, Md. : 1950)213/ 1, 86-9510.4049/jimmunol.2300175The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood. Thus, unknown regulators of the NLRP3 inflammasome, which are associated with CAPS development, are being investigated. To identify novel components of the NLRP3 inflammasome, we performed a high-throughput screen using a human protein array, with NLRP3 as the bait. We identified a NLRP3-binding protein, which we called the cryopyrin-associated nano enhancer (CANE). We demonstrated that CANE increased IL-1β secretion after NLRP3 inflammasome reconstitution in human embryonic kidney 293T cells and formed a "speck" in the cytosol, a hallmark of NLRP3 inflammasome activity. Reduced expression of endogenous CANE decreased IL-1β secretion upon stimulation with the NLRP3 agonist nigericin. To investigate the role of CANE in vivo, we developed CANE-transgenic mice. The PBMCs and bone marrow-derived macrophages of CANE-transgenic mice exhibited increased IL-1β secretion. Moreover, increased autoinflammatory neutrophil infiltration was observed in the s.c. tissue of CANE-transgenic versus wild-type mice; these phenotypes were consistent with those of CAPS model mice. These findings suggest that CANE, a component of the NLRP3 inflammasome, is a potential modulator of the inflammasome and a contributor to CAPS pathogenesis.
  2. Tumor Necrosis Factor and Interleukin-1β Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation.2023/07/03Ishitoku Michinori,Mokuda Sho,Araki Kei,Watanabe Hirofumi,Kohno Hiroki,Sugimoto Tomohiro,Yoshida Yusuke,Sakaguchi Takemasa,Masumoto Junya,Hirata Shintaro,Sugiyama EijiViruses15/ 710.3390/v15071498Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) and the auxiliary receptor Neuropilin-1 (NRP1) to enter host cells. NRP1 has another isoform, NRP2, whose function in COVID-19 has seldom been reported. In addition, although patients with severe cases of COVID-19 often exhibit increased levels of proinflammatory cytokines, the relationship between these cytokines and SARS-CoV-2 proliferation remains unknown. The aim of this study is to clarify the roles of proinflammatory cytokines in Neuropilin expressions and in SARS-CoV-2 infection. To identify the expression patterns of NRP under inflamed and noninflamed conditions, next-generation sequencing (RNA-seq), immunohistochemistry, quantitative real-time PCR, and Western blotting were performed using primary cultured fibroblast-like synoviocytes, MH7A (immortalized cell line of human rheumatoid fibroblast-like synoviocytes), immortalized MRC5 (human embryonic lung fibroblast), and synovial tissues. To measure viral proliferative capacity, SARS-CoV-2 infection experiments were also performed. NRP2 was upregulated in inflamed tissues. Cytokine-stimulated human fibroblast cell lines, such as MH7A and immortalized MRC5, revealed that NRP2 expression increased with co-stimulation of tumor necrosis factor α (TNFα) and interleukin-1 beta (IL-1β) and was suppressed with anti-TNFα antibody alone. TNFα and IL-1β promoted SARS-CoV-2 proliferation and Spike protein binding. The viral proliferation coincided with the expression of NRP2, which was modulated through plasmid transfections. Our results revealed that proinflammatory cytokines, including TNFα, contribute to NRP2 upregulation and SARS-CoV-2 proliferation in host human cells.
  3. Bioprosthetic Valve Deterioration: Accumulation of Circulating Proteins and Macrophages in the Valve Interstitium.2023/07Sakaue Tomohisa,Koyama Tadaaki,Nakamura Yoshitsugu,Okamoto Keitaro,Kawashima Takayuki,Umeno Tadashi,Nakayama Yasuhide,Miyamoto Shinji,Shikata Fumiaki,Hamaguchi Mika,Aono Jun,Kurata Mie,Namiguchi Kenji,Uchita Shunji,Masumoto Junya,Yamaguchi Osamu,Higashiyama Shigeki,Izutani HironoriJACC. Basic to translational science8/ 7, 862-88010.1016/j.jacbts.2023.01.003Histologic evaluations revealed excessive accumulations of macrophages and absence of fibroblastic interstitial cells in explanted bioprosthetic valves. Comprehensive gene and protein expression analysis and histology unveiled an accumulation of fibrinogen and plasminogen, an activator of infiltrated macrophages, from degenerated valve surfaces in the interstitial spaces. These pathologies were completely reproduced in a goat model replaced with an autologous pericardium-derived aortic valve. Further preclinical animal experiments using goats demonstrated that preventing infiltration of macrophages and circulating proteins by increasing collagen density and leaflet strength is an effective treatment option.
  4. Expression of factor XIII originating from synovial fibroblasts and macrophages induced by interleukin-6 signaling.2023/01/06Watanabe Hirofumi,Mokuda Sho,Tokunaga Tadahiro,Kohno Hiroki,Ishitoku Michinori,Araki Kei,Sugimoto Tomohiro,Yoshida Yusuke,Yamamoto Toshihiro,Matsumoto Mayuko,Masumoto Junya,Hirata Shintaro,Sugiyama EijiInflammation and regeneration43/ 1, 210.1186/s41232-022-00252-4Blood coagulation factor XIII (FXIII) promotes cross-linking between fibrin molecules at the final stage of the blood coagulation cascade. However, its expression in cells or tissues and function, particularly factor XIII subunit B (FXIII-B), remains controversial. Hemorrhagic FXIII deficiency following anti-interleukin-6 (IL-6) receptor antibody treatment has been reported in patients with rheumatoid arthritis (RA). Patients receiving this biologics have reduced FXIII activity when compared to the activity in those treated with other biologics. The relationship between pro-inflammatory cytokines and FXIII expression remains unknown.To investigate the expression pattern of FXIII in synovial tissues, immunohistochemistry, RT-qPCR, and western blotting were performed. FXIII-A expressed monocyte-derived macrophages were treated with recombinant IL-6 and anti-IL-6 receptor antibody. RNA sequencing of FXIII-B-overexpressing cells was performed to clarify the function of FXIII-B.The immunohistochemical analysis of synovial tissues revealed that factor XIII subunit A (FXIII-A) was expressed in M2 macrophages, and FXIII-B was expressed in fibroblast-like synoviocytes. IL-6 stimulation upregulated FXIII-A expression in IL-4-induced monocyte-derived macrophages, and the anti-IL-6 receptor antibody suppressed FXIII-A expression. FXIII-B was more abundantly secreted in the supernatant of fibroblast-like synoviocytes compared with that of other cells. RNA sequencing showed that FXIII-B elevated the expression of genes associated with anti-apoptotic molecules and chemokines.Our findings highlight that synovial tissue is one of the sources of FXIII production. We also have demonstrated IL-6-dependent FXIII-A expression and the novel potential functions of FXIII-B.
  5. Intestinal edema induced by LPS-induced endotoxemia is associated with an inflammasome adaptor ASC.2023Yamamoto Toshihiro,Kurata Mie,Kaneko Naoe,Masumoto JunyaPloS one18/ 2, e028174610.1371/journal.pone.0281746The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/caspase-1/interleukin(IL)-1β axis, also known as the inflammasome pathway, is indispensable for IL-1β activation in response to various pathogens or own damages. Previously, we developed an NLRP3-inflammasome using a cell-free system and identified ASC targeting drugs; thus, examination of ASC-related histopathology in various diseases could help to provide indications for these drugs. Here, we generated mice deficient only in ASC-protein (ASC-deficient (AD) mice) using CRISPR/Cas9 technology, studied which tissues were most affected, and obtained histopathological images of lipopolysaccharide (LPS)-induced endotoxemia. C57BL/6 wild-type (WT) and (AD) mice were injected intraperitoneally with a lethal dose (50 μg/g) of LPS. Statistical analysis of the survival of C57BL/6 mice and AD mice was performed using the Kaplan-Meier method and the log-rank test. The histopathological findings of multiple tissues from these mice were compared. Acute inflammation (e.g., catarrhal inflammation), along with congestion was observed in the colon of WT mice but not in that of AD mice. Adhesion of neutrophils to capillaries, along with interstitial infiltration, were observed in multiple tissues from WT mice. In AD mice, neutrophil infiltration was less severe but remained evident in the stomach, small intestine, heart, liver, kidney, spleen, and brain. Notably, there was no difference between WT and AD mice with respect to alveolar neutrophil infiltration and interstitial edema. These findings suggest that even though ASC contributes to systemic inflammation, it is dependent on the tissue involved. Intestinal congestion and edema might be good candidates for anti-ASC-targeted therapy.
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担当授業科目

  1. 2024早期医療体験実習
  2. 2024解析病理学 講義・演習・実習
  3. 2024医科学研究Ⅳ
  4. 2024臨床実習（導入型）
  5. 2024臨床実習（選択型）
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所属学協会

  1. 日本リウマチ学会
  2. 日本炎症・再生医学会
  3. 日本病理学会
  4. 日本臨床検査医学会
  5. 日本免疫学会
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委員歴

  1. 2024/05/17-現在日本病理学会理事・中国四国支部・支部長
  2. 2024/04/01-現在東京外国語大学アジア・アフリカ言語文化研究所フィールドサイエンス学際領域専門委員会委員
  3. 2020/06-現在日本免疫不全・自己炎症学会学会誌編集委員長
  4. 2020/06-2024/03/31日本病理学会中国四国支部・幹事(学術委員長)
  5. 2017/06-現在日本免疫不全・自己炎症学会理事
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