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

Wechsler, J. B.; Szabo, A.; Hsu, C. L.; Krier-Burris, R. A.; Schroeder, H. A.; Wang, M. Y.; Carter, R. G.; Velez, T. E.; Aguiniga, L. M.; Brown, J. B.; Miller, M. L.; Wershil, B. K.; Barrett, T. A.; Bryce, P. J.

Mucosal Immunol. 2018 Jan 25


Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as 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 interleukin-6 (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 with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2(-/-) x H4R(-/-) mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2(-/-) mice, revealing an innate protective antibacterial 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.Mucosal Immunology advance online publication, 24 January 2018; doi:10.1038/mi.2017.121.

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