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

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

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49 Scopus citations


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 '/' × 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.

Original languageEnglish
Pages (from-to)861-870
Number of pages10
JournalMucosal Immunology
Issue number3
StatePublished - May 1 2018

Bibliographical note

Publisher Copyright:
© The Author(s) 2018.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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