Peritoneal mast cell-derived IL-10 promotes peritoneal-colon tolerance by reprogramming macrophages to ameliorate colitis

Maintaining peripheral tolerance is critical for mucosal homeostasis. The peritoneal cavity (PerC), a gut-adjacent immune niche exposed to microbial products, contains mast cells (MCs) whose regulatory role in colitis is unclear. Here we show that IL-10 derived from MCs restrains colitis by programming anti-inflammatory macrophages along the PerC-colon axis. Reconstitution of MC-deficient mice with wild-type (WT) bone marrow-derived mast cells (BMMCs), but not Il10 −/− BMMCs, alleviated colitis. Mechanistically, WT MCs reduced TNF-α + macrophages and neutrophil infiltration while increasing IL-10 + macrophages in the PerC and promoting the accumulation of GATA6 + IL-10 + macrophages in the colon, without affecting Th1/Th17 responses. LPS-stimulated WT MCs induced IL-10 production in peritoneal macrophages via an IL-10-dependent mechanism. Depletion of PerC macrophages largely abolished protection and reduced GATA6 + IL-10 + macrophage accumulation in the colon. Collectively, these findings define an innate immunity-driven pathway of peripheral tolerance operating at the PerC-colon interface and identify the MC-IL-10-macrophage circuit as a potential target for early attenuation of intestinal inflammation.