Background and Aims: Liver fibrosis is the common pathological pathway of chronic liver diseases and its mechanisms of which have not been fully declared. Macrophages play essential roles in progression of liver fibrosis partially by sensing abnormal mechanical signals. The aim of the study is to investigate the functions of macrophage Piezo1, a mechano-sensitive ion channel, in liver fibrosis. Approach and Results: Immunofluorescence in human and murine fibrotic liver samples revealed that expression of macrophage Piezo1 was increased. Myeloid-specific Piezo1 knockout (Piezo1ΔLysM) attenuated liver fibrosis by decreased collagen deposition and epithelial-mesenchymal transition (EMT). In Piezo1ΔLysM mice, less inflammation during development of liver fibrosis was observed by lessened macrophage infiltration, decreased M1 polarization and expression of inflammatory cytokines. RNA-seq data showed macrophage Piezo1 regulated transcription of cathepsin S (CTSS). Piezo1ΔLysM inhibited expression and activity of CTSS in vitro and in vivo and regulated T cell activity. Furthermore, inhibition of CTSS reversed macrophage inflammatory response driven by Piezo1 activation and LPS. Macrophage Piezo1 activation promoted CTSS secretion due to increased activity of Ca2+-dependent calpain protease induced by Ca2+ influx to cleave lysosome-associated membrane protein-1 (LAMP1). Pharmacological inhibition of calpain activity partially blocked Piezo1 mediated CTSS secretion. Conclusions: Macrophage Piezo1 deficiency limits the progression of liver fibrosis by inhibited inflammatory response and decreased secretion of CTSS. These findings suggest that targeting Piezo1 channel may be a potential strategy for treating hepatic fibrosis.

中文翻译：

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巨噬细胞中 Piezo1 的特异性缺失可保护小鼠肝纤维化的进展。

背景与目的：肝纤维化是慢性肝病常见的病理途径，其机制尚未完全阐明。巨噬细胞部分通过感知异常机械信号在肝纤维化进展中发挥重要作用。本研究的目的是研究巨噬细胞 Piezo1（一种机械敏感离子通道）在肝纤维化中的功能。方法和结果：人类和小鼠纤维化肝脏样本中的免疫荧光显示巨噬细胞 Piezo1 的表达增加。骨髓特异性 Piezo1 敲除 (Piezo1ΔLysM) 通过减少胶原沉积和上皮间质转化 (EMT) 来减轻肝纤维化。在 Piezo1ΔLysM 小鼠中，通过减少巨噬细胞浸润、降低 M1 极化和炎性细胞因子的表达，观察到肝纤维化发展过程中炎症减少。RNA-seq 数据显示巨噬细胞 Piezo1 调节组织蛋白酶 S (CTSS) 的转录。Piezo1ΔLysM 在体外和体内抑制 CTSS 的表达和活性，并调节 T 细胞活性。此外，抑制 CTSS 可以逆转由 Piezo1 激活和 LPS 驱动的巨噬细胞炎症反应。由于 Ca2+ 流入诱导 Ca2+ 依赖性钙蛋白酶裂解溶酶体相关膜蛋白 1 (LAMP1) 的活性增加，巨噬细胞 Piezo1 激活促进了 CTSS 分泌。钙蛋白酶活性的药理学抑制部分阻断了 Piezo1 介导的 CTSS 分泌。结论：巨噬细胞 Piezo1 缺陷通过抑制炎症反应和减少 CTSS 分泌来限制肝纤维化的进展。这些发现表明，靶向 Piezo1 通道可能是治疗肝纤维化的潜在策略。