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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. Here, 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 highlight the significance of the novel mouse model in fibrosis research.

Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.

Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-γ (IFN-γ) receptor on ILC2 cells in vivo. IFN-γ effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue-resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo.