Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis

Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear since targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R(−/−) mice had lower symptom scores, neutrophil-recruitment mediators (colonic IL-6, CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient Kit(W-sh/W-sh) mice reconstituted with histidine decarboxylase–deficient (HDC(−/−)) bone marrow–derived MCs compared to WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2(−/−)×H4R(−/−) mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2(−/−) mice, revealing an innate protective anti-bacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.