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