MrgprD ‐mediated macrophage polarization drives chemically induced colitis in mice

Abstract Inflammatory bowel disease (IBD) is characterized by aberrant immune responses in the gut. Mas‐related G protein‐coupled receptor D (MrgprD), which is primarily expressed in sensory neurons of the dorsal root ganglia (DRG), is known to promote neuroinflammation. However, its potential role in driving intestinal inflammation remains undefined. Here, we show that systemic Mrgprd KO alleviated dextran sodium sulfate (DSS)‐induced acute colitis. We found that MrgprD was expressed in colonic macrophages and DSS treatment increased its expression. Mrgprd global deletion reduced macrophage infiltration in the colon and suppressed their pro‐inflammatory M1 polarization following DSS challenge. Using conditional KO mouse lines, we further demonstrate that myeloid‐specific Mrgprd deletion conferred stronger protection than its neuronal deletion. This is evidenced by preserved colon length, reduced histopathology scores, improved barrier integrity, and decreased M1 macrophage proportions. Notably, neuron‐specific, but not myeloid‐specific, Mrgprd KO accelerated intestinal motility under physiological conditions. MrgprD deficiency reduced M1‐associated gene expression and suppressed NF‐κB signaling activation in both colonic lamina propria cells and bone marrow‐derived macrophages (BMDMs), whereas activation of MrgprD by its agonist enhanced these responses in BMDMs. Bioinformatic analysis further supports the involvement of the MRGPRD‐NF‐κB signaling axis in human IBD. Collectively, our findings identify MrgprD as a novel driver of acute colitis, acting primarily through NF‐κB‐mediated pro‐inflammatory macrophage polarization in the colon. © 2026 The Pathological Society of Great Britain and Ireland.