Mechanosensory channel Piezo1 is essential in pathogenic T cellmediated intestinal inflammation

Abstract Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the gastrointestinal tract. CD4+ T cells are especially known to be the main drivers of IBD when they show an elevated level of activation. Elevation of intracellular Ca2+ is one of the key triggering signals for T cell activation. Piezo1 is a mechanosensitive nonselective Ca2+-permeable cation channel, which is broadly expressed in mammalian cells. However, the role of Piezo1 in the pathogenesis of T cell-mediated colitis remains unknown. We have generated T cell-specific Piezo1 knockout (Piezo1fl/flxCD4-cre) mice and observed that loss of Piezo1 in CD4+ T cell increased Th1 and Th17 cell polarization. RNA-sequence analysis of Piezo1fl/flxCD4-cre T cells identified elevated pathogenic Th17 cell pathway, IFN-γ signaling pathways and inflammatory response gene signature compared to that of wild type. These results suggest that Piezo1 controls the inflammatory response of pathogenic T cells. Next, we examined the function of Piezo1 on intestinal inflammation in vivo using acute and chronic colitis mouse model. For the acute colitis mouse model, we used a chemically induced mouse model of colitis using DSS in drinking water. Piezo1fl/flxCD4-cre mice with DSS developed severe colitis compared to Piezo1fl/fl mice with DSS. However, in chronic colitis mouse model, which is the adaptive transfer of naïve CD4+ T cells (CD4+CD45RBhigh) from Piezo1fl/fl or Piezo1fl/flxCD4cre into Rag1−/− mice, T cells from Piezo1fl/flxCD4cre mice failed to induce colon inflammation, while mice that received T cells from Piezo1fl/fl mice developed severe intestinal inflammation. Thus, our data demonstrate a critical role of Piezo1 in CD4+ T cell-mediated intestinal inflammation. Supported by R03 CA230840, P30 CA043703, St. Baldrick’s Foundation, Hyundai Hope-on-Wheels Scholar Hope Grant, Andrew McDonough B+ Foundation, Curing Kids Cancer, Center for Pediatric Immunotherapy at Rainbow