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Mas\u2010related G protein\u2010coupled 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\n                    <jats:italic>Mrgprd<\/jats:italic>\n                    KO alleviated dextran sodium sulfate (DSS)\u2010induced acute colitis. We found that MrgprD was expressed in colonic macrophages and DSS treatment increased its expression.\n                    <jats:italic>Mrgprd<\/jats:italic>\n                    global deletion reduced macrophage infiltration in the colon and suppressed their pro\u2010inflammatory M1 polarization following DSS challenge. Using conditional KO mouse lines, we further demonstrate that myeloid\u2010specific\n                    <jats:italic>Mrgprd<\/jats:italic>\n                    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\u2010specific, but not myeloid\u2010specific,\n                    <jats:italic>Mrgprd<\/jats:italic>\n                    KO accelerated intestinal motility under physiological conditions. MrgprD deficiency reduced M1\u2010associated gene expression and suppressed NF\u2010\u03baB signaling activation in both colonic lamina propria cells and bone marrow\u2010derived macrophages (BMDMs), whereas activation of MrgprD by its agonist enhanced these responses in BMDMs. Bioinformatic analysis further supports the involvement of the MRGPRD\u2010NF\u2010\u03baB signaling axis in human IBD. Collectively, our findings identify MrgprD as a novel driver of acute colitis, acting primarily through NF\u2010\u03baB\u2010mediated pro\u2010inflammatory macrophage polarization in the colon. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70125","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:36:03Z","timestamp":1790825763000},"page":"521-539","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>MrgprD<\/scp>\n                    \u2010mediated macrophage polarization drives chemically induced colitis in mice"],"prefix":"10.1002","volume":"270","author":[{"given":"Yiping","family":"Lv","sequence":"first","affiliation":[{"name":"School of Life Sciences Nanjing Normal University  Nanjing PR 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 Nanjing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongxiang","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Medicine Nanjing University of Chinese Medicine  Nanjing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyi","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Bloomberg School of Public Health, Johns Hopkins University  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-6600","authenticated-orcid":false,"given":"Lei","family":"Lan","sequence":"additional","affiliation":[{"name":"School of Life Sciences Nanjing Normal University  Nanjing PR 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