Alveolar epithelial cell-derived Sonic hedgehog promotes pulmonary fibrosis through OPN-dependent alternative macrophage activation

Jiwei Hou, Jie Ji, Xiang Chen, Honghui Cao, Yi Tan, Yu Cui, Zou Xiang, Xiaodong Han

Research output: Journal article publicationJournal articleAcademic researchpeer-review


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.

Original languageEnglish
JournalFEBS Journal
Publication statusE-pub ahead of print - 13 Dec 2020


  • alveolar type II cells
  • idiopathic pulmonary fibrosis
  • macrophage alternative activation
  • osteopontin
  • Sonic hedgehog

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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