Piezo1-specific Deletion in Macrophage Protects the Progression of Chronic Inflammatory Bowel Disease in Mice.

Background & aims: Piezo1, a recently identified mechanically activated nonselective cation channel protein, demonstrates sensitivity to various mechanical stimuli, such as matrix stiffness and shear stress. Although accumulating evidence implicates Piezo1 channels in numerous physiologic and pathophysiologic processes, its involvement in dextran sulfate sodium (DSS)-induced acute and chronic inflammatory bowel disease (IBD) remains incompletely understood. This study aimed to investigate the effect of Piezo1 channels in macrophage polarization and its associated functions in IBD.

Methods: DSS-induced inflammatory bowel disease model was established in Piezo1^td/Tdt or Piezo1^fl/fl and Piezo1^△LysM male mice. Additionally, bone marrow-derived macrophages from Piezo1^fl/fl and Piezo1^△LysM male mice were isolated to elucidate the downstream targets of Piezo1 and the associated underlying molecular mechanisms.

Results: Our findings revealed that Piezo1 deficiency in macrophages could protect mice from DSS-induced chronic IBD, as evidenced by improved colon length and the preservation of colon structure. The mitigation of inflammation during chronic IBD progression was observed with Piezo1 deficiency in macrophages, characterized by reduced macrophage accumulation, M1 macrophage polarization, T helper 1 infiltration, and decreased inflammatory cytokine secretion. Further investigations unveiled that Piezo1-deficient macrophages inhibit the expression and activity of Nod-like receptor protein 3 and nuclear factor kappa B in colon tissues and bone marrow-derived macrophages while regulating the nuclear translocation of p65. Conversely, macrophage Piezo1 activation enhanced inflammatory cytokine secretion by activating Nod-like receptor protein 3/nuclear factor kappa B pathways.

Conclusions: Myeloid Piezo1 mediates colonic immune response, and disrupting Piezo1 inhibits the progression of chronic IBD. This study provides hitherto undocumented evidence of the pivotal role of macrophage Piezo1 channels in regulating the progression of chronic IBD. Targeting macrophage Piezo1 may offer a promising therapeutic strategy against chronic IBD.