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

Joshua Brian 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, Jeffrey B Brown, M. L. Miller, Barry K Wershil, T. A. Barrett, P. J. Bryce*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)861-870
Number of pages10
JournalMucosal Immunology
Volume11
Issue number3
DOIs
StatePublished - May 1 2018

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Histamine Receptors
Colitis
Histamine
Inflammation
Ulcerative Colitis
Mast Cells
Neutrophil Infiltration
Oxazolone
Histidine Decarboxylase
Bacterial Translocation
Dextran Sulfate
Adaptive Immunity
Granulocytes
Peroxidase
Interleukin-6
Colon
Mucous Membrane
Neutrophils
Bone Marrow
Immunohistochemistry

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Wechsler, J. B., Szabo, A., Hsu, C. L., Krier-Burris, R. A., Schroeder, H. A., Wang, M. Y., ... Bryce, P. J. (2018). Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis. Mucosal Immunology, 11(3), 861-870. https://doi.org/10.1038/mi.2017.121
Wechsler, Joshua Brian ; 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, Jeffrey B ; Miller, M. L. ; Wershil, Barry K ; Barrett, T. A. ; Bryce, P. J. / Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis. In: Mucosal Immunology. 2018 ; Vol. 11, No. 3. pp. 861-870.
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abstract = "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.",
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Wechsler, JB, Szabo, A, Hsu, CL, Krier-Burris, RA, Schroeder, HA, Wang, MY, Carter, RG, Velez, TE, Aguiniga, LM, Brown, JB, Miller, ML, Wershil, BK, Barrett, TA & Bryce, PJ 2018, 'Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis', Mucosal Immunology, vol. 11, no. 3, pp. 861-870. https://doi.org/10.1038/mi.2017.121

Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis. / Wechsler, Joshua Brian; 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, Jeffrey B; Miller, M. L.; Wershil, Barry K; Barrett, T. A.; Bryce, P. J.

In: Mucosal Immunology, Vol. 11, No. 3, 01.05.2018, p. 861-870.

Research output: Contribution to journalArticle

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T1 - Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis

AU - Wechsler, Joshua Brian

AU - Szabo, A.

AU - Hsu, C. L.

AU - Krier-Burris, R. A.

AU - Schroeder, H. A.

AU - Wang, M. Y.

AU - Carter, R. G.

AU - Velez, T. E.

AU - Aguiniga, L. M.

AU - Brown, Jeffrey B

AU - Miller, M. L.

AU - Wershil, Barry K

AU - Barrett, T. A.

AU - Bryce, P. J.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

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