Bone morphogenetic protein 4 alleviates pulmonary fibrosis by regulating macrophages.

Fibrosis is a pathological change mainly characterized by an increase of fibrous connective tissue and decrease of parenchymal cells. Its continuous progress may lead to the destruction of organ structure and function decline. An excess of alternatively activated M2 macrophages have been considered crucial candidates in the progression of fibrosis. Bone morphogenetic proteins (BMPs), a group of multifunctional growth factors, are essential for organ development and pathophysiological process, however, the roles that BMPs play in innate immune homeostasis in the development of fibrosis and the downstream signals have not been fully explored. In the current study, we firstly found that the expression of BMP4 was significantly down-regulated in human and mouse fibrosis samples. Then we investigated the effects of BMP4 on macrophage polarization in IL-4 environment and related molecular mechanisms, and found that BMP4 caused a decrease in polarized response towards M2, reflected in the expression of the markers Fizz1, Ym1 and Arg1, together with an inhibition in Stat6 phosphorylation. This relied on the Smad1/5/8 signaling, which had a crosstalk with Stat6. Moreover, the in vivo study showed that BMP4 treatment can reduce collagen deposition and delay the development of experimental pulmonary fibrosis in mice by inhibiting M2 macrophages through adoptive transfer experiment. These findings revealed a novel role of BMP4 in regulating macrophages, offering potential strategies for treating pulmonary fibrosis.