Mast Cells Regulate Epithelial Barrier Integrity and Myeloid Immune Responses in Experimental Colitis

Mast cells (MCs) are increasingly recognized as modulators of intestinal homeostasis and inflammation; however, their precise contribution during colitis remains incompletely defined. Here, we investigated the role of MCs in dextran sulfate sodium (DSS)‐induced colitis using a Kit‐independent MC‐deficient model (Cpa3‐Cre; Mcl1 fl/fl ), in which selective deletion of the anti‐apoptotic gene Mcl1 ablates MCs. Despite efficient and tissue‐wide MC depletion, MC‐deficient mice exhibited macroscopic and histological disease severity comparable to control mice. However, MC deficiency significantly altered epithelial and immune responses during acute intestinal injury. Specifically, MC‐deficient mice displayed increased colonic MUC2 expression, together with decreased tight‐junction integrity. The impaired epithelial barrier was associated with increased bacterial infiltration and selective accumulation of myeloid cells, including neutrophils, dendritic cells, and macrophages, alongside increased TNF‐α and reduced VEGF levels. Systemically, in DSS‐treated mice, MC deficiency was associated with splenomegaly and increased splenic neutrophils and dendritic cells. Importantly, adoptive transfer of bone marrow‐derived MCs restored the epithelial barrier‐associated features and reduced neutrophil accumulation. Collectively, these findings identify MCs as key regulators of epithelial–myeloid crosstalk contributing to the maintenance of barrier integrity and limiting excessive myeloid accumulation and bacterial exposure rather than acting as primary drivers of tissue injury.