Journal
FEBS JOURNAL
Volume 288, Issue 11, Pages 3530-3546Publisher
WILEY
DOI: 10.1111/febs.15669
Keywords
alveolar type II cells; idiopathic pulmonary fibrosis; macrophage alternative activation; osteopontin; Sonic hedgehog
Categories
Funding
- National Natural Science Foundation of China [81570059]
- Natural Science Foundation of Jiangsu Province of China [BK20151398]
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The study revealed the interaction between macrophages and fibrosis-associated alveolar epithelial cells, unveiling the mechanism of macrophage polarization and pulmonary fibrosis development, and suggesting Shh as a potential target for treating pulmonary fibrosis.
The alternative activation of macrophages in the lungs has been considered as a major factor promoting pulmonary fibrogenesis; however, the mechanisms underlying this phenomenon are still elusive. In this study, we investigated the interaction between macrophages and fibrosis-associated alveolar epithelial cells using a bleomycin-induced mouse pulmonary fibrosis model and a coculture system. We demonstrated that fibrosis-promoting macrophages are spatially proximate to alveolar type II (ATII) cells, permissive for paracrine-induced macrophage polarization. Importantly, we revealed that fibrosis-associated ATII cells secrete Sonic hedgehog (Shh), a hedgehog pathway ligand, and that ATII cell-derived Shh promotes the development of pulmonary fibrosis by osteopontin (OPN)-mediated macrophage alternative activation. Mechanistically, Shh promotes the secretion of OPN in macrophages via Shh/Gli signaling cascade. The secreted OPN acts on the surrounding macrophages in an autocrine or paracrine manner and induces macrophage alternative activation through activating the JAK2/STAT3 signaling pathway. Tissue samples from idiopathic pulmonary fibrosis patients confirmed the increased expression of Shh and OPN in ATII cells and macrophages, respectively. Together, our study illustrated an alveolar epithelium-dependent mechanism for macrophage M2 polarization and pulmonary fibrogenesis and suggested that targeting Shh may offer a selective and efficient therapeutic strategy for the development and progression of pulmonary fibrosis.
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