IRAK-M Promotes Alternative Macrophage Activation and Fibroproliferation in Bleomycin-Induced Lung Injury

摘要: Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed contribution macrophages. Recently, TLR signaling has been identified as regulator IL-1R-associated kinase-M (IRAK-M), MyD88-dependent inhibitor signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient IRAK-M (IRAK-M(-/-)) were protected against bleomycin-induced displayed diminished collagen deposition association reduced production IL-13 compared wild-type (WT) control mice. Bone marrow chimera experiments indicated that expression bone marrow-derived cells, rather than promoted After bleomycin, WT macrophages an alternatively activated phenotype, whereas IRAK-M(-/-) higher classically macrophage markers. Using vitro coculture system, isolated from vivo bleomycin-challenged WT, not IRAK-M(-/-), mice increased α-smooth muscle actin fibroblasts IL-13-dependent fashion. Finally, upregulated peripheral blood idiopathic correlated markers alternative activation. These data indicate skews toward profibrotic which promotes production, leading progression experimental