Role of IL-21 in the development of autoimmune myositis

• Project/Area Number: 17K09995
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Chiba University
• Principal Investigator: Suto Akira 千葉大学, 大学院医学研究院, 准教授 (50447306)
• Co-Investigator(Kenkyū-buntansha): 鈴木 浩太郎 千葉大学, 大学院医学研究院, 准教授 (90554634)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: IL-21 / γδT細胞 / 自己免疫性筋炎 / GM-CSF

Outline of Final Research Achievements

IL-21 is involved in the development of various autoimmune diseases; however, the role of IL-21 in autoimmune inflammatory myopathies remains unknown. Here, we found that serum levels of IL-21 were significantly elevated in patients with inflammatory myopathies. Upon the induction of experimental autoimmune myositis (EAM), muscle weakness was less obvious in IL-21-deficient (IL-21-/-) mice as compared to that in wild-type mice. GM-CSF from γδT cells was significantly reduced in EAM-induced IL-21-/- mice. The severity of EAM was attenuated by GM-CSF neutralization or γδT cell-deficiency. Majority of muscle-infiltrating γδT cells expressed Vγ4+Vδ4+ TCR and exhibited CX3CR1high phenotype. The induction of Cx3cl1, a ligand for CX3CR1, in the muscles by EAM was reduced in IL-21-/- mice. Taken together, these results suggest that IL-21 facilitates autoimmune myositis through the accumulation of GM-CSF-producing Vγ4+Vδ4+ cells in the muscles possibly via CX3CR1/CX3CL1 pathways.

Academic Significance and Societal Importance of the Research Achievements

本研究の特色は、炎症性筋疾患発症におけるIL-21の役割に着目していることである。本研究者は以前よりIL-21の産生機構、及び自己免疫疾患におけるIL-21の役割に関する研究に従事し、多くの実績を残している。本申請研究は、炎症性筋疾患モデルにIL-21が関与していることをIL-21欠損マウスを用いた研究で明らかにし、さらに炎症性筋疾患患者で血清中IL-21濃度が高いことを見出しており、炎症性筋疾患の病態にIL-21が関与していることが強く示唆される。本申請研究は、炎症性筋疾患の治療法の開発に繋がる可能性も高く、その臨床的意義は大きいと考える。

Research Products

• [Int'l Joint Research] Children's Hospital of Philadelphia(米国)
• [Journal Article] Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells (2020)
  • Author(s): Suehiro Ken-Ichi、Suto Akira、Suga Kensuke、Furuya Hiroki、Iwata Arifumi、Iwamoto Taro、Tanaka Shigeru、Kageyama Takahiro、Suzuki Kotaro、Hirose Koichi、Lefebvre V?ronique、Nakajima Hiroshi
  • Journal Title: Cellular & Molecular Immunology Volume: 0 Issue: 7 Pages: 0-0
  • DOI: 10.1038/s41423-020-0384-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Experience of musculoskeletal ultrasound scanning improves physicians’ physical examination skills in assessment of synovitis (2020)
  • Author(s): Saku Aiko, Furuta Shunsuke, Kato Manami, Furuya Hiroki, Suzuki Kazumasa, Fukuta Masashi, Suehiro Kenichi, Makita Sohei, Tamachi Tomohiro, Ikeda Kei, Takatori Hiroaki, Maezawa Yuko, Suto Akira, Suzuki Kotaro, Hirose Koichi, Nakajima Hiroshi.
  • Journal Title: Clinical Rheumatology Volume: 39 Issue: 4 Pages: 1091-1099
  • DOI: 10.1007/s10067-020-04960-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] γδ T cells enhance TSLP production and ILC2 accumulation in house dust mite-induced allergic airway inflammation (2020)
  • Author(s): Saku A, Hirose K, Kageyama T, Kono K, Nakamura K, Yokota M, Maezawa Y, Suto A, Nakajima H.
  • Journal Title: Allergology International Volume: 69 Issue: 1 Pages: 132-135
  • DOI: 10.1016/j.alit.2019.05.010
  • NAID: 130007788677
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] IL-21 enhances mast cell accumulation in the intestine and exacerbates the development of experimental food allergy. (2019)
  • Author(s): Kono K, Hirose K, Makita S, Kageyama T, Tamachi T, Saku A, Suto A, Suzuki K, Nakajima H.
  • Journal Title: Clin Exp Allergy. Volume: 49(11) Issue: 11 Pages: 1523-1526
  • DOI: 10.1111/cea.13473
  • Peer Reviewed
• [Journal Article] Fucosyltransferase 2 induces lung epithelial fucosylation and exacerbates house dust mite-induced airway inflammation. (2019)
  • Author(s): Saku A, Hirose K, Ito T, Iwata A, Sato T, Kaji H, Tamachi T, Suto A, Goto Y, Domino SE, Narimatsu H, Kiyono H, Nakajima H
  • Journal Title: J Allergy Clin Immunol. Volume: 144(3) Issue: 3 Pages: 698-709
  • DOI: 10.1016/j.jaci.2019.05.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Matrix metalloproteinase-12 produced by Ly6Clow macrophages prolongs the survival after myocardial infarction by preventing neutrophil influx. (2019)
  • Author(s): Kubota A, Suto A, Suzuki K, Kobayashi Y, Nakajima H.
  • Journal Title: J Mol Cell Cardiol. Volume: - Pages: 41-52
  • DOI: 10.1016/j.yjmcc.2019.04.007
  • Peer Reviewed
• [Journal Article] Successful Treatment for Refractory Interstitial Lung Disease and Pneumomediastinum With Multidisciplinary Therapy Including Tofacitinib in a Patient With Anti-MDA5 Antibody-Positive Dermatomyositis. (2019)
  • Author(s): Kato M, Ikeda K, Kageyama T, Kasuya T, Kumagai T, Furuya H, Furuta S, Tamachi T, Suto A, Suzuki K, Nakajima H.
  • Journal Title: J Clin Rheumatol. Volume: - Issue: 8S Pages: S574-S577
  • DOI: 10.1097/rhu.0000000000000984
  • Peer Reviewed
• [Journal Article] Sox12 promotes T reg differentiation in the periphery during colitis. (2018)
  • Author(s): anaka S, Suto A, Iwamoto T, Kageyama T, Tamachi T, Takatori H, Suzuki K, Hirose K, Ohara O, Lefebvre V, Nakajima H.
  • Journal Title: J Exp Med. Volume: 215 Issue: 10 Pages: 2509-2519
  • DOI: 10.1084/jem.20172082
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analyses of dermal innate lymphoid cells in mice lacking T-bet and STAT6 (2018)
  • Author(s): Makita S, Takatori H, Tamachi T, Suto A, Suzuki K, Nakajima H.
  • Journal Title: Allergology International Volume: 67 Issue: Supplement.1 Pages: S51-S53
  • DOI: 10.1016/j.alit.2018.05.004
  • NAID: 130007485242
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production (2017)
  • Author(s): Matsuki A, Takatori T, Makita S, Yokota M, Tamachi T, Suto A, Suzuki K, Hirose K, Nakajima H
  • Journal Title: J. Allergy Clin. Immunol Volume: 印刷中 Issue: 4 Pages: 31023-31025
  • DOI: 10.1016/j.jaci.2016.08.022
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF?Producing γδ T Cells in the Muscle (2017)
  • Author(s): Kageyama Takahiro、Suto Akira、Iwamoto Taro、Tanaka Shigeru、Suehiro Kenichi、Yokoyama Yusuke、Saku Aiko、Furuta Shunsuke、Ikeda Kei、Suzuki Kotaro、Hirose Koichi、Nakajima Hiroshi
  • Journal Title: ImmunoHorizons Volume: 1 Issue: 8 Pages: 176-187
  • DOI: 10.4049/immunohorizons.1700053
  • Peer Reviewed
• [Journal Article] IkBNS enhances follicular helper T-cell differentiation and function downstream of ASCL2. (2016)
  • Author(s): Hosokawa J, Suzuki K, Meguro K, Tanaka S, Maezawa Y, Suto A, Fujimura L, Sakamoto A, Clevers H, Ohara O, Nakajima H.
  • Journal Title: J Allergy Clin Immunol. Volume: S0091-6749 Issue: 1 Pages: 32476-32479
  • DOI: 10.1016/j.jaci.2016.10.047
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Sox12 suppresses the production of Th2 cytokines through the degradation of GATA3 in Th2 cell (2019)
  • Author(s): Ken-ichi Suehiro, Akira Suto, Hiroshi Nakajima
  • Organizer: 日本免疫学会
• [Presentation] TCR-mediated Sox12 induction promotes peripherally induced T regulatory cell differentiation under inflammatory conditions. (2018)
  • Author(s): Shigeru Tanaka, Suto Akira, Takahiro Kageyama, Tomohiro Tamachi, Kotaro Suzuki, Koichi Hirose, and Hiroshi Nakajima.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Roles of Sox12 in the development of peripherally induced Treg cells. (2018)
  • Author(s): Suto A
  • Organizer: The 2nd Chiba University - UC San Diego Symposium on Mucosal Immunology,
  • Int'l Joint Research
• [Remarks] 千葉大学 大学院医学研究院 アレルギー・臨床免疫学ホームページ
  • URL: https://www.m.chiba-u.ac.jp/dept/allergy-clin-immunol/
• [Remarks] 千葉大学大学院医学研究院 アレルギー・臨床免疫学 研究業績
  • URL: http://www.m.chiba-u.jp/dept/allergy-clin-immunol/research/