Role of ILC2 in idiopathic interstitial pneumonia

2022 Fiscal Year Final Research Report

• Project/Area Number: 18H05286
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Review Section: Broad Section I
• Research Institution: Osaka University
• Principal Investigator: Moro Kazuyo 大阪大学, 大学院医学系研究科, 教授 (90468489)
• Project Period (FY): 2018-06-11 – 2023-03-31
• Keywords: 肺線維症 / ILC2 / IL-33

Outline of Final Research Achievements

Pulmonary fibrosis (PF) is characterised by inflammation and collagen deposition in the alveolar interstitium, leading to dyspnoea and death. However, the comprehensive pathogenesis of PF remains unclear due to the lack of spontaneous fibrosis mouse models. We found that Ifngr1-/-Rag2-/- mice, lacking the mechanisms to suppress group 2 and 3 innate lymphoid cells (ILC2s and ILC3s), developed severe PF spontaneously. In Ifngr1-/-Rag2-/- mice, Il1rl1hiIl13hi-ILC2 subpopulation was increased at disease-onset phase before collagen production began. Further, defects in ILCs or IL-33, the strong ILC2 activator, prevented PF development. ILC2s directly induce collagen production by fibroblasts in vitro, and fibroblasts started to produce IL-33 in the chronic phase, presumably forming a positive feedback loop between fibroblasts and ILC2s leading to irreversible fibrosis. Moreover, the increased IL1RL1 and IL13 and decreased IFNGR1 expression levels in ILC2s from human idiopathic PF patients.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

Ifngr1-/-Rag2-/-マウスにおける線維化の誘導は、内因性因子によって発症する線維化の理解を促進すると期待している。これまでの線維症研究の多くはブレオマイシン投与によって、上皮細胞におけるＤＮＡ損傷誘導するモデルマウスに支えられてきたが、このモデルでは内因性因子がどのように線維化に働くかを評価できなかった。線維化には複合的な因子が働くと考えられていることから、Ifngr1-/-Rag2-/-マウスを用いた研究は今後の線維化研究を加速させると期待される。