The ASIC3-M-CSF-M2 macrophage-positive feedback loop modulates fibroblast-to-myofibroblast differentiation in skin fibrosis pathogenesis

作者：Jun‐Jie Wu, Zi‐Li Sun, Siyu Liu, Zhonghua Chen, Zheng‐Dong Yuan, Ming‐Li Zou, Ying‐Ying Teng, Yueyue Li, Dan‐Yang Guo, Feng‐Lai Yuan · 发表于：Cell Death and Disease · 年份：2022 · DOI：10.1038/s41419-022-04981-9 · 被引用次数：22 · 研究领域：Wound Healing and Treatments、Skin and Cellular Biology Research、Tendon Structure and Treatment

Inflammation is one of the main pathological features leading to skin fibrosis and a key factor leading to the progression of skin fibrosis. Acidosis caused by a decrease in extracellular pH is a sign of the inflammatory process. Acid-sensing ion channels (ASICs) are ligand-gated ion channels on the cell membrane that sense the drop in extracellular pH. The molecular mechanisms by which skin fibroblasts are regulated by acid-sensing ion channel 3 (ASIC3) remain unknown. This study investigated whether ASIC3 is related to inflammation and skin fibrosis and explored the underlying mechanisms. We demonstrate that macrophage colony-stimulating factor (M-CSF) is a direct target of ASIC3, and ASIC3 activation promotes M-CSF transcriptional regulation of macrophages for M2 polarization. The polarization of M2 macrophages transduced by the ASIC3-M-CSF signal promotes the differentiation of fibroblasts into myofibroblasts through transforming growth factor β1 (TGF-β1), thereby producing an ASIC3-M-CSF-TGF-β1 positive feedback loop. Targeting ASIC3 may be a new treatment strategy for skin fibrosis.