Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu, 214041, China.
The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu, 214041, China.
Cell Death Dis. 2022 Jun 6;13(6):527. doi: 10.1038/s41419-022-04981-9.
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.
炎症是导致皮肤纤维化的主要病理特征之一，也是皮肤纤维化进展的关键因素。细胞外 pH 值降低引起的酸中毒是炎症过程的一个标志。酸敏离子通道（ASICs）是细胞膜上的配体门控离子通道，可感知细胞外 pH 值的下降。ASIC3 调节皮肤成纤维细胞的分子机制尚不清楚。本研究探讨了 ASIC3 是否与炎症和皮肤纤维化有关，并探讨了其潜在机制。我们证明集落刺激因子（M-CSF）是 ASIC3 的直接靶标，ASIC3 的激活促进了巨噬细胞中 M-CSF 的转录调节，促进了 M2 极化。ASIC3-M-CSF 信号转导的 M2 巨噬细胞的极化通过转化生长因子β1（TGF-β1）促进成纤维细胞向肌成纤维细胞分化，从而产生 ASIC3-M-CSF-TGF-β1 正反馈环。靶向 ASIC3 可能是治疗皮肤纤维化的一种新策略。
