Role of ARIH2 in the inflammasome-related cardiovascular disease

• Project/Area Number: 18K08112
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Takahashi Masafumi 自治医科大学, 医学部, 教授 (40296108)
• Co-Investigator(Kenkyū-buntansha): 木村 博昭 自治医科大学, 医学部, 講師 (70593622) ; 唐澤 直義 自治医科大学, 医学部, 講師 (60631893) ; 渡邊 幸子 自治医科大学, 医学部, 助教 (80770619) ; 鎌田 諒 慶應義塾大学, 政策・メディア研究科(藤沢), 研究員 (60801420)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 炎症反応 / サイトカイン / 心血管病 / タンパク質修飾 / タンパク質分解 / 炎症 / インフラマソーム / ユビキチン

Outline of Final Research Achievements

NLRP3 inflammasome is a multiprotein complex that regulates IL-1β release and contributes to sterile inflammatory responses. We previously identified an E3 ligase ARIH2 that interacts with NLRP3 and negatively regulates inflammasome activity. In this study, because systemic deletion of ARIH2 is embryonic lethal in mice, we generated macrophage-specific ARIH2-deficient mice and showed that NLRP3 protein level was increased in ARIH2-deficient macrophages. We further showed that glucose regulates NLRP3 inflammasome activation in response to hypoxia through KATP channel-mediated K+ efflux. Furthermore, using a murine model of Kawasaki disease induced by CAWS, we showed that NLRP3 inflammasome contributes to the development of Kawasaki disease-like vasculitis.

Academic Significance and Societal Importance of the Research Achievements

NLRP3インフラマソームの活性化の制御機構や病態への関与については、未だ不明な点も多く、これを標的とした治療応用に向けても様々な課題が残されている。本研究の成果により、NLRP3インフラマソームの活性化の新たな分子機構が明らかにされたことは学術的な意義がある。また、川崎病の病因についても未だ不明であることから、その血管炎惹起の分子機序の一部を示すことができたことは社会的な意義もあると考えられる。

Research Products

• [Journal Article] NLRP3 Inflammasome as a Common Denominator of Atherosclerosis and Abdominal Aortic Aneurysm (2021)
  • Author(s): Takahashi Masafumi
  • Journal Title: Circulation Journal Volume: 85 Issue: 12 Pages: 2129-2136
  • DOI: 10.1253/circj.CJ-21-0258
  • NAID: 130008119971
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2021-11-25
  • Peer Reviewed
• [Journal Article] Calciprotein Particles Induce IL-1β/α?Mediated Inflammation through NLRP3 Inflammasome-Dependent and -Independent Mechanisms (2021)
  • Author(s): Anzai Fumiya、Karasawa Tadayoshi、Komada Takanori、Yamada Naoya、Miura Yutaka、Sampilvanjil Ariunaa、Baatarjav Chintogtokh、Fujimura Kenta、Matsumura Takayoshi、Tago Kenji、Kurosu Hiroshi、Takeishi Yasuchika、Kuro-O Makoto、Takahashi Masafumi
  • Journal Title: ImmunoHorizons Volume: 5 Issue: 7 Pages: 602-614
  • DOI: 10.4049/immunohorizons.2100066
  • Peer Reviewed / Open Access
• [Journal Article] NLRP3 inflammasome as a common denominator of atherosclerosisand abdominal aortic aneurysm. (2021)
  • Author(s): Takahashi Masafumi
  • Journal Title: Circulation Journal Volume: -
  • Peer Reviewed
• [Journal Article] NLRP3 inflammasome as a key driver of vascular disease. (2021)
  • Author(s): Takahashi Masafumi
  • Journal Title: Cardiovascular Research Volume: -
  • Peer Reviewed
• [Journal Article] NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury (2020)
  • Author(s): Ito Homare、Kimura Hiroaki、Karasawa Tadayoshi、Hisata Shu、Sadatomo Ai、Inoue Yoshiyuki、Yamada Naoya、Aizawa Emi、Hishida Erika、Kamata Ryo、Komada Takanori、Watanabe Sachiko、Kasahara Tadashi、Suzuki Takuji、Horie Hisanaga、Kitayama Joji、Sata Naohiro、Yamaji-Kegan Kazuyo、Takahashi Masafumi
  • Journal Title: The Journal of Immunology Volume: 205 Issue: 5 Pages: 1393-1405
  • DOI: 10.4049/jimmunol.2000217
  • Peer Reviewed / Open Access
• [Journal Article] GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition (2020)
  • Author(s): Aizawa Emi、Karasawa Tadayoshi、Watanabe Sachiko、Komada Takanori、Kimura Hiroaki、Kamata Ryo、Ito Homare、Hishida Erika、Yamada Naoya、Kasahara Tadashi、Mori Yoshiyuki、Takahashi Masafumi
  • Journal Title: iScience Volume: 23 Issue: 5 Pages: 101070-101070
  • DOI: 10.1016/j.isci.2020.101070
  • Peer Reviewed / Open Access
• [Journal Article] ASC regulates platelet activation and contributes to thrombus formation independent of NLRP3 inflammasome (2020)
  • Author(s): Watanabe Sachiko、Usui-Kawanishi Fumitake、Komada Takanori、Karasawa Tadayoshi、Kamata Ryo、Yamada Naoya、Kimura Hiroaki、Dezaki Katsuya、Ohmori Tsukasa、Takahashi Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 531 Issue: 2 Pages: 125-132
  • DOI: 10.1016/j.bbrc.2020.07.063
  • Peer Reviewed
• [Journal Article] Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages. (2020)
  • Author(s): 1)Watanabe S, Usui-Kawanishi F, Karasawa, Kimura H, Kamata R, Inoue, Mise N, Kasahara T, Takahashi M
  • Journal Title: J Cell Physiol Volume: - Issue: 10 Pages: 7554-7566
  • DOI: 10.1002/jcp.29659
  • Peer Reviewed
• [Journal Article] Role of the NLRP3 Inflammasome in Preeclampsia (2020)
  • Author(s): Shirasuna Koumei、Karasawa Tadayoshi、Takahashi Masafumi
  • Journal Title: Frontiers in Endocrinology Volume: 11 Pages: 80-80
  • DOI: 10.3389/fendo.2020.00080
  • Peer Reviewed / Open Access
• [Journal Article] GSDME-dependentincomplete pyroptosis permits selective IL-1α release under caspase-1 inhibition (2020)
  • Author(s): Aizawa E, Karasawa T, Watanabe S, Komada T, Kimura H, Kamata R, ItoH, Hishida E, Yamada N, Kasahara T, Mori Y, Takahashi M
  • Journal Title: iScience Volume: －
• [Journal Article] Glucose regulates hypoxia-induced NLRP3inflammasome activation in macrophages (2020)
  • Author(s): Watanabe S, Usui-Kawanishi F, Karasawa T, Kimura H, Kamata R, InoueY, Mise N, Kasahara T, Takahashi M
  • Journal Title: Journal of Cellular Physiology Volume: －
  • Peer Reviewed
• [Journal Article] Crucial role of NLRP3 inflammasome in a murine model of Kawasaki disease. (2020)
  • Author(s): 4)Anzai F, Watanabe S, Kimura H, Kamata R, Karasawa T, Komada T, Nakamura J, Nagi-Miura N, Ohno N, Takeishi Y, Takahashi M
  • Journal Title: J Mol Cell Cardiol Volume: 138 Pages: 185-196
  • DOI: 10.1016/j.yjmcc.2019.11.158
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of inflammasome adaptor protein ASC enhances functional recovery after spinal cord injury in mice (2020)
  • Author(s): Shiraishi Y, Kimura A, Kimura H, Ohmori T, Takahashi M, Takeshita K
  • Journal Title: Journal of Orthopaedic Science Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] Palmitic acid activates NLRP3 inflammasome and induces placental inflammation during pregnancy in mice (2020)
  • Author(s): SANO Michiya、SHIMAZAKI Sayaka、KANEKO Yasuaki、KARASAWA Tadayoshi、TAKAHASHI Masafumi、OHKUCHI Akihide、TAKAHASHI Hironori、KUROSAWA Akira、TORII Yasushi、IWATA Hisataka、KUWAYAMA Takehito、SHIRASUNA Koumei
  • Journal Title: Journal of Reproduction and Development Volume: 66 Issue: 3 Pages: 241-248
  • DOI: 10.1262/jrd.2020-007
  • NAID: 130007853972
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Role of NLRP3 Inflammasome in Cardiac Inflammation and Remodeling after Myocardial Infarction (2019)
  • Author(s): Takahashi Masafumi
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 4 Pages: 518-523
  • DOI: 10.1248/bpb.b18-00369
  • NAID: 130007622154
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-04-01
  • Peer Reviewed / Open Access
• [Journal Article] IL-1β Plays an Important Role in Pressure Overload-Induced Atrial Fibrillation in Mice (2019)
  • Author(s): Matsushita N, Ishida N, Ibi M, Saito M, Takahashi M, Taniguchi S, Iwakura Y, Morino Y, Taira E, Sawa Y, Hirose M
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 4 Pages: 543-546
  • DOI: 10.1248/bpb.b18-00363
  • NAID: 130007622152
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-04-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammasome-independent and atypical processing of IL-1β contributes to acid aspiration-induced acute lung injury. (2019)
  • Author(s): 5)Mizushina Y, Karasawa T, Aizawa K, Kimura H, Watanabe S, Kamata R, Komada T, Mato N, Kasahara T, Koyama S, Bando M, Hagiwara K, Takahashi M
  • Journal Title: J Immunol Volume: 203 Issue: 1 Pages: 236-246
  • DOI: 10.4049/jimmunol.1900168
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of NLRP3 inflammasome in the development of peritoneal dialysis-related peritoneal fibrosis. (2019)
  • Author(s): 6)Hishida E, Ito H, Komada T, Karasawa T, Kimura H, Watanabe S, Kamata R, Aizawa E, Kasahara T, Morishita Y, AkimotoT, Nagata D, Takahashi M
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 10363-10363
  • DOI: 10.1038/s41598-019-46504-1
  • Peer Reviewed / Open Access
• [Journal Article] Role of TLR5 in inflammation and tissue damage after intestinal ischemia-reperfusion injury. (2019)
  • Author(s): 7)Ito H, Sadatomo A, Inoue Y, Yamada N, Aizawa E, Hishida E, Kamata R, Karasawa T, Kimura H, Watanabe S, Komada T, Horie H, Kitagawa J, Sata N, Takahashi M
  • Journal Title: Biochem Biophys Res Commun Volume: 519 Issue: 1 Pages: 15-22
  • DOI: 10.1016/j.bbrc.2019.08.083
  • Peer Reviewed / Open Access
• [Journal Article] Cell-Specific Roles of NLRP3 Inflammasome in Myocardial Infarction (2019)
  • Author(s): Takahashi Masafumi
  • Journal Title: Journal of Cardiovascular Pharmacology Volume: 74 Issue: 3 Pages: 188-193
  • DOI: 10.1097/fjc.0000000000000709
• [Journal Article] Saturated fatty acid-crystals activate NLRP3 inflammasome (2019)
  • Author(s): Karasawa Tadayoshi、Takahashi Masafumi
  • Journal Title: Aging Volume: 11 Issue: 6 Pages: 1613-1614
  • DOI: 10.18632/aging.101892
  • Peer Reviewed / Open Access
• [Journal Article] Innate immunity as a target for acute cardioprotection (2019)
  • Author(s): Zuurbier Coert J、Abbate Antonio、Cabrera-Fuentes Hector A、Cohen Michael V、Collino Massimo、De Kleijn Dominique P V、Downey James M、Pagliaro Pasquale、Preissner Klaus T、Takahashi Masafumi、Davidson Sean M
  • Journal Title: Cardiovascular Research Volume: 115 Issue: 7 Pages: 1131-1142
  • DOI: 10.1093/cvr/cvy304
  • Peer Reviewed / Open Access
• [Journal Article] Guidelines for evaluating myocardial cell death (2019)
  • Author(s): Mishra Paras K.、Adameova Adriana、Hill Joseph A.、Baines Christopher P.、Kang Peter M.、Downey James M.、Narula Jagat、Takahashi Masafumi、Abbate Antonio、Piristine Hande C.、Kar Sumit、Su Shi、Higa Jason K.、Kawasaki Nicholas K.、Matsui Takashi
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: 317 Issue: 5 Pages: H891-H922
  • DOI: 10.1152/ajpheart.00259.2019
  • Peer Reviewed / Open Access
• [Journal Article] Cutting Edge: G Protein Subunit b 1 Negatively Regulates NLRP3 Inflammasome Activation (2019)
  • Author(s): Tomohiko Murakami, Lerdluck Ruengsinpinya, Eriko Nakamura,Yoshifumi Takahata, Kenji Hata, Hiroaki Okae,Shun’ichiro Taniguchi, Masafumi Takahashi and Riko Nishimura
  • Journal Title: The Journal of Immunology Volume: 202 Issue: 7 Pages: 1942-1947
  • DOI: 10.4049/jimmunol.1801388
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Implications of immune-inflammatory responses in smooth muscle dysfunction and disease (2019)
  • Author(s): Usui-Kawanishi Fumitake、Takahashi Masafumi、Sakai Hiroyasu、Suto Wataru、Kai Yuki、Chiba Yoshihiko、Hiraishi Keizo、Kurahara Lin Hai、Hori Masatoshi、Inoue Ryuji
  • Journal Title: Journal of Smooth Muscle Research Volume: 55 Issue: 0 Pages: 81-107
  • DOI: 10.1540/jsmr.55.81
  • NAID: 130007795217
  • ISSN: 0916-8737, 1884-8796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exogenous nanoparticles and endogenous crystalline molecules as danger signals for the?NLRP3 inflammasomes (2018)
  • Author(s): Shirasuna Koumei、Karasawa Tadayoshi、Takahashi Masafumi
  • Journal Title: Journal of Cellular Physiology Volume: 234 Issue: 5 Pages: 5436-5450
  • DOI: 10.1002/jcp.27475
  • Peer Reviewed
• [Journal Article] Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in MacrophagesHighlights (2018)
  • Author(s): Karasawa Tadayoshi、Kawashima Akira、Usui-Kawanishi Fumitake、Watanabe Sachiko、Kimura Hiroaki、Kamata Ryo、Shirasuna Koumei、Koyama Yutaro、Sato-Tomita Ayana、Matsuzaka Takashi、Tomoda Hiroshi、Park Sam-Yong、Shibayama Naoya、Shimano Hitoshi、Kasahara Tadashi、Takahashi Masafumi
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 38 Issue: 4 Pages: 744-756
  • DOI: 10.1161/atvbaha.117.310581
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease. (2018)
  • Author(s): Nakamura J, Watanabe S, Kimura H, Kobayashi M, Karasawa T, Kamata R, Usui-Kawanishi F, Sadatomo A, Mizukami H, Nagi-Miura N, Ohno N, Kasahara T, Minota S, Takahashi M.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 7601-7601
  • DOI: 10.1038/s41598-018-25856-0
  • Peer Reviewed / Open Access
• [Presentation] 様々な病態における無菌性炎症とインフラマソーム (2022)
  • Author(s): 髙橋将文
  • Organizer: 第5回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] 老化関連疾患における慢性炎症とインフラマソーム (2021)
  • Author(s): 高橋将文、駒田敬則.
  • Organizer: 第66回日本透析医学会学術集会
  • Invited
• [Presentation] AIM2-dependent pyroptosis is crucial for resolution after rhabdomyolysis-induced acute kidney injury (2021)
  • Author(s): Chintogtokh Baatarjav, Takanori Komada, Masafumi Takahashi.
  • Organizer: 64th Annual meeting of the Japanese Society of Nephrology
• [Presentation] NLRP3 Inflammasome Promotes Vasculitis of Kawasaki Disease. (2020)
  • Author(s): 安齋文弥
  • Organizer: AHA Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] 腹膜線維症におけるNLRP3ｚインフラマソームの役割 (2019)
  • Author(s): 菱田英里華、駒田敬則、秋元哲、高橋将文、長田太助
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] 飽和脂肪酸は結晶形成を介して好中球浸潤を誘導する (2019)
  • Author(s): 唐澤直義、渡邊幸子、笠原忠、高橋将文
  • Organizer: 第51回日本動脈硬化学会総会・学術集会
• [Presentation] アセトアミノフェン急性肝不全におけるFerroptosisの分子機構 (2019)
  • Author(s): 山田直也、唐澤直義、駒田敬則、木村博昭、伊藤準哉、仲川清隆、桑田浩、原俊太郎、佐久間康成、佐田尚宏、高橋将文
  • Organizer: 第33回肝類洞壁細胞研究会学術集会
• [Presentation] 循環器領域における無菌性炎症とインフラマソーム：薬物治療の現況と創薬への展望 (2019)
  • Author(s): 高橋将文
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 動脈硬化の進展におけるNLRP3インフラマソームの役割 (2019)
  • Author(s): 唐澤直義
  • Organizer: 第40回日炎症・再生医学会
• [Presentation] 循環器領域における無菌性炎症とインフラマソーム：薬物治療の現況と創薬への展望． (2019)
  • Author(s): 高橋将文
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 腸管虚血再灌流障害におけるNLRP3インフラマソームの役割の解明． (2018)
  • Author(s): 伊藤誉、佐田友藍、井上賢之、鎌田諒、渡邊幸子、唐澤直義、木村博昭、佐田尚宏、高橋将文．
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] 慢性腎臓病病態でのAbsent in melanoma2を介した無菌性炎症． (2018)
  • Author(s): 駒田敬則、Muruve Daniel、高橋将文．
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] 低酸素刺激によるNLRP3インフラマソーム活性化機構の解明 (2018)
  • Author(s): 渡邊幸子、河西文武、木村博昭、唐澤直義、鎌田諒、高橋将文．
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] IL-β阻害薬と動脈硬化・発がん． (2018)
  • Author(s): 高橋将文
  • Organizer: 第50回日本動脈硬化学会総会
• [Presentation] 脂肪細胞分化におけるLMP7の役割． (2018)
  • Author(s): 木村博昭、唐澤直義、渡邊幸子、鎌田諒、駒田敬則、笠原忠、高橋将文．
  • Organizer: 第39回日本肥満学会
• [Presentation] 動脈硬化・大動脈瘤形成におけるNLRP3インフラマソームの役割． (2018)
  • Author(s): 高橋将文．
  • Organizer: 第59回日本脈管学会総会
• [Presentation] ARIH2によるユビキチン修飾を介したNLRP3インフラマソーム抑制機構． (2018)
  • Author(s): 川島晃、鈴木幸一、高橋将文．
  • Organizer: 第41回日本分子生物学会年会
• [Book] 循環器内科 87 (2020)
  • Author(s): 安齋文弥、高橋将文
  • Publisher: 科学評論社
• [Remarks] 自治医科大学 分子病態治療研究センター 炎症・免疫研究部
  • URL: https://www.jichi.ac.jp/inflammation/
• [Remarks] 自治医科大学 分子病態治療研究センター 炎症・免疫研究部
  • URL: http://www.jichi.ac.jp/inflammation/