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

Abstract

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; Mcl1fl/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.