Piezo1 promotes colitis progression by modulating the Nrf2/NF-κB/NLRP3 signaling pathway

Inflammatory bowel disease (IBD) is a type of chronic inflammatory disorders. The main pathological features of IBD include immune homeostasis disorder and intestinal epithelial barrier dysfunction, which jointly lead to the deterioration of IBD. Mechanosensation refers to the ability of an organism to sense mechanical stimuli (such as pressure, pulling and shearing forces) and make adaptive responses, which plays an important role in the peristalsis and dilation of the intestines. Piezo1 is a mechanosensitive ion channel which is highly expressed in macrophages in the lamina propria of the colon, and closely related to the development of colonic inflammatory injury. However, it remains unclear how the mechanical sensing property of Piezo1 plays a role in the occurrence and development of IBD. Therefore, we investigated the role of Piezo1 in the pathophysiology of intestinal inflammation and its effects on modulating the Nrf2/NF-κB/NLRP3 signaling pathway. Wild-type and Piezo1^fl/flLyz2^cre ulcerative colitis model was established by oral administration of 5 % dextran sulfate sodium (DSS), and the mice were monitored for changes in body weight, faeces, and other living conditions. Single-cell sequencing indicated that Piezo1 was highly expressed in macrophages from ulcerative colitis tissues. RNA sequencing showed a reduction in NFκB expression levels when Piezo1 expression was inhibited in mouse colonic lamina propria macrophages, suggesting that Piezo1 could play an important role in DSS-induced inflammatory responses in mouse colons by regulating NFκB. Piezo1 inhibitors effectively reduced pathological damage of colonic tissue, inflammatory factor release, and oxidative stress levels, such as ROS and MDA levels; aided in maintaining normal intestinal barrier function; and had significant protective effects on DSS-induced colitis in mice. This study identify the critical role of Piezo1 in colitis development in mice. Piezo1 can exacerbate inflammatory damage in colonic tissues by modulating the Nrf2/NF-κB/NLRP3 signaling pathway, thereby promoting colitis development in mice.