Abstract：
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.
摘要：
纤维化是以纤维结缔组织增多和实质细胞减少为主要特征的病理变化。其不断进步可能导致器官结构破坏和功能下降。过量的可替代活化的M2巨噬细胞被认为是纤维化进展中的关键候选物。骨形态发生蛋白(BMPs),一组多功能生长因子，对器官发育和病理生理过程至关重要，然而,BMP在先天免疫稳态中在纤维化发展中的作用及其下游信号尚未得到充分研究.在目前的研究中,我们首先发现BMP4的表达在人和小鼠纤维化样本中显著下调。然后研究了BMP4对IL-4环境中巨噬细胞极化的影响及相关分子机制,并发现BMP4引起对M2的极化反应降低，反映在标记物Fizz1，Ym1和Arg1的表达中，同时抑制了Stat6磷酸化。这依赖于Smad1/5/8信令，与Stat6相声。此外，体内研究表明，BMP4治疗可以通过过继转移实验抑制M2巨噬细胞，减少胶原沉积，延缓小鼠实验性肺纤维化的发展。这些发现揭示了BMP4在调节巨噬细胞中的新作用，提供治疗肺纤维化的潜在策略。
