Roles for TNFR superfamily molecules in regulation of ILC function

• Project/Area Number: 16K15508
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Tohoku University
• Principal Investigator: ISHII Naoto 東北大学, 医学系研究科, 教授 (60291267)
• Co-Investigator(Kenkyū-buntansha): 宗 孝紀 富山大学, 大学院医学薬学研究部(薬学), 教授 (60294964)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 自然リンパ球 / サイトカイン / 補助刺激シグナル / アレルギー / GITR / 炎症 / 免疫学

Outline of Final Research Achievements

Group 2 innate lymphoid cells (ILC2) in the lung are activated by inhaled allergens and epithelial cytokine interleukin 33 (IL-33). We found that IL-33 alone was not sufficient to induce optimal ILC2 activation and that additional signals from glucocorticoid-induced TNFR-related protein (GITR) were essential. Gitr -/- mice displayed reduced numbers of ILC2 after administration of papain or IL-33, which resulted in impaired expression of IL-5 and IL-13 and diminished eosinophilia in the lung. Crosslinking of GITR with IL-33 synergistically activated NF-κB, p38, and Erk to induce IL-9 production, and autocrine IL-9 promoted IL-5 and IL-13 via STAT5. Accordingly, STAT5 activators, IL-2 and IL-9, restored the defective responses of Gitr -/- ILC2. Our results identify a previously unknown critical role for GITR co-signaling in initiating and promoting early ILC2 activation in the lung.

Research Products

• [Int'l Joint Research] University of Perugia(Italy)
• [Int'l Joint Research] University of Hawaii(U.S.A.)
• [Journal Article] TRAF2 and TRAF5 associated with the signal transducing receptor gp130 limit IL-6-driven transphosphorylation of JAK1 through the inhibition of proximal JAK-JAK interaction. (2018)
  • Author(s): Kimura M, Nagashima H, Okuyama Y, Ishii N, and So T
  • Journal Title: Int. Immunol Volume: - Issue: 7 Pages: 219-299
  • DOI: 10.1093/intimm/dxy029
  • Peer Reviewed
• [Journal Article] TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation. (2018)
  • Author(s): Machiyama T, So T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Harigae H, Ishii N.
  • Journal Title: Biochem Biophys Res Commun. Volume: - Issue: 3 Pages: 544-550
  • DOI: 10.1016/j.bbrc.2018.03.186
  • Peer Reviewed
• [Journal Article] GITR cosignal in ILC2s controls allergic lung inflammation. (2018)
  • Author(s): Nagashima H, Okuyama Y, Fujita T, Takeda T, Motomura Y, Moro K, Hidaka T, Omori K, Sakurai T, Machiyama T, Ndhlovu LC, Riccardi C, So T, Ishii N.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 5 Pages: 1939-1943.e8
  • DOI: 10.1016/j.jaci.2018.01.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury (2017)
  • Author(s): Lan P, Fan Y, Zhao Y, Lou X, Monsour HP, Zhang X, Choi Y, Dou Y, Ishii N, Ghobrial RM, Xiao X, Li XC
  • Journal Title: J Clin Invest. Volume: 127 Issue: 6 Pages: 2222-2234
  • DOI: 10.1172/jci91075
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ES Stress Protein CHOP Mediates Insulin Resistanse by Modulating Adipose Tissue Macrophage Polarity. (2017)
  • Author(s): Suzuki T, Gao J, Ishigaki Y, Kondo K, Sawada S, Izumi T, Uno K, Kaneko K, Tsukita S, Takahashi K, Asao A, Ishii N, Imai J, Yamada T, Oyadomarai S, Katagiri H
  • Journal Title: Cell Rep Volume: 18 Issue: 8 Pages: 2045-2057
  • DOI: 10.1016/j.celrep.2017.01.076
  • Peer Reviewed / Open Access
• [Journal Article] TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development (2016)
  • Author(s): Nagashima, H., Okuyama, Y., Hayashi, T., Ishii, N., So, T.
  • Journal Title: J Immunol Volume: 196 Issue: 10 Pages: 4082-4089
  • DOI: 10.4049/jimmunol.1501610
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] TRAF2 and TRAF5 binding to the signal transducing receptor gp130 inhibit JAK1 activation in the IL-6-receptor signaling complex (2017)
  • Author(s): Masanobu Kimura, Hiroyuki Nagashima, Naoto Ishii, Takanori So
  • Organizer: 日本免疫学会学術集会
• [Presentation] Early activation of group 2 innate lymphoid cells in the lung is critically controlled by the TNFR superfamily molecule GITR (2017)
  • Author(s): Takanori So, Hiroyuki Nagashima, Yuko Okuyama, Yasutaka Motomura, Kazuyo Moro, Lishomwa C. Ndhlovu, Carlo Riccardi, Naoto Ishii
  • Organizer: 日本免疫学会学術集会
• [Presentation] A new regulator of OX40 co-signaling controls autoimmune neuroinflammation mediated by CD4+ T cells (2017)
  • Author(s): Yuko Okuyama, Hiroyuki Nagashima, Masuko Ushio-Fukao, Michael Croft, Naoto Ishii, Takanori So
  • Organizer: 日本免疫学会学術集会
• [Presentation] TNF receptor-associated factors 5 expressed in non-hematopoietic cells augments acute colonic damage induced by dextran sulfate (2017)
  • Author(s): HAI T PHUNG, Hiroyuki Nagashima, Yuko Okuyama, Shuhei Kobayashi, Atsuko Asao, Naoto Ishii, Takanori So
  • Organizer: 日本免疫学会学術集会