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A4345 - ILC2 Promotes Bleomycin-Induced Pulmonary Fibrosis Though IL-33/ST2 Signaling Pathway
Author Block: Y. Zhao1, T. Liu2, F. Gonzalez De Los Santos2, Z. Wu2, S. H. Phan2; 1Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China, 2Pathology, University of Michigan, Ann Arbor, MI, United States.
Recent evidence suggests that bone marrow (BM)-derived hematopoietic progenitor cells play an important role in lung injury and fibrosis. While IL-33/ST2 signal transduction is implicated in multiple pathogenic processes, such as inflammation, tissue injury/repair, fibrosis and scleroderma, ST2-expressing type 2 innate lymphoid cells (ILC2) are involved in tissue wound healing/remodeling, including lung fibrosis. However, the precise role of ILC2 in the pathogenesis of fibrotic lung disease remains unclear. In this study the role of ILC2 in the mouse bleomycin (BLM)-induced lung fibrosis model is analyzed. Lung fibrosis was induced in the WT control (C57BL/6) and ST2 KO mice by injecting BLM endotracheally. The results showed that ILC2 number was significantly increased in the injured lungs compared to controls, which correlated with a significant increase in ST2+ cell number. In contrast, ST2+ cells were decreased significantly in BM after BLM treatment. In WT mice BLM caused significant increases in lung mRNA levels of IL-33 and ST2, and recruitment of ILC2, which accompanied the expected pulmonary fibrosis. In contrast ST2 KO mice showed diminished ILC2 recruitment with significantly attenuated lung fibrosis and myofibroblast differentiation. Compared with WT controls, BLM-induced ILC2-associated cytokines IL-13 and amphiregulin expression were significantly decreased in ST2 KO mice. To further confirm the importance of BM-derived ILC2 in lung fibrosis, ST2 KO-BM chimera mice were generated through reconstitution of lethally irradiated recipient WT mice with donor BM cells from ST2 KO mice. The BLM-induced increase of lung ILC2 was absent in ST2 KO BM chimera mice, along with the complete suppression of BLM-induced lung IL-13, amphiregulin and TGFβ mRNA expression. Notably, ST2 KO BM chimera mice showed significantly attenuated lung fibrosis. Moreover, lineage- (Lin-) BM cells from BLM-treated WT mice stimulated type I collagen expression in co-cultured lung fibroblasts, which was not observed when co-cultured with Lin- BM cells from ST2 KO mice. Interestingly, TGFβ was highly induced in the Lin- BM cells from BLM-treated WT, but not ST2 KO mice. Taken together, the data suggested that BM-derived ILC2 were recruited to fibrotic lung through IL33/ST2 pathway, and contributed to fibroblast activation to promote the development of lung fibrosis.