Pannexin-1 Aggravates Inflammatory Bowel Disease via Unbalancing Macrophage Polarisation and Triggering Ferroptosis in Mice.

Abstract

Inflammatory bowel disease (IBD) is characterised by chronic inflammation in the gastrointestinal tract resulting from dysregulated immune responses to gut microflora. Intestinal macrophages play important roles in the pathogenesis of IBD. The progression of IBD is often associated with increased M1-like macrophages, whereas M2-like macrophages are linked to tissue repair and resolution of inflammation. Ferroptosis in macrophages is potentially involved in IBD pathogenesis. However, the mechanisms underlying the involvement of macrophages and ferroptosis in IBD remain incompletely understood. Here, we established a dextran sodium sulphate (DSS)-induced murine colitis model to recapitulate human IBD. We observed elevated Pannexin-1 (Panx1) expression and an increased M1/M2 macrophage ratio in colonic tissues of DSS-treated mice. Depletion of Panx1 improved DSS-induced colitis via promoting macrophage polarisation into the M2-like phenotype. Furthermore, Panx1 depletion significantly enhanced M2-like macrophage polarisation and moderately inhibited M1-like macrophage polarisation. We further found that depletion of Panx1 reduced ferroptosis in intestinal macrophages from DSS-treated mice, and Glutathione peroxidase 4 (GPX4), a suppressor of ferroptosis, was upregulated in M2-like macrophages rather than M1-like macrophages by Panx1 depletion. In vitro assays showed that depletion of Panx1 inhibited ferroptosis in bone marrow-derived macrophage (BMDM)-derived macrophages. Further analysis showed that Wilms' tumour 1-associating protein (WTAP) inhibited Panx1 expression. Collectively, Panx1 aggravates IBD by shifting macrophage polarisation towards a pro-inflammatory phenotype and enhancing ferroptosis. Our study provides a novel mechanism of IBD pathogenesis and suggests potential therapeutic targets such as Panx1 and macrophage polarisation for IBD.