1. Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
2. The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
3. Department of Pathology, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310006, China.
4. The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China.
5. Innovation Research Center, Shandong University of Chinese Medicine, Jinan, 250307, China.
6. School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, UK.
# These authors contribute equally.
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.
Keywords: liver fibrosis, Piezo1, macrophage, inflammation, cathepsin S