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

Abstract

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 KitW-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.

Mouse Colonic Epithelial Cells Functionally Express the Histamine H4 Receptor

“…This effect is mediated by the H 4 R, since it is totally blocked by addition of the H 4 R-specific antagonist JNJ7777120 (Thurmond et al, 2004) and since it is absent in epithelial layers generated from H 4 R-deficient mice. Thus, mouse colon epithelial cells functionally express the H 4 R. This conclusion is in direct contrast to that of the study by Wechsler et al, who did not detect any H 4 R mRNA expression in EpCAM + mouse colon epithelial cells (Wechsler et al, 2018). A possible reason is the low abundance of H 4 R mRNA in mouse colon epithelial cells.…”

Establishment and Characterization of a Murine Mucosal Mast Cell Culture Model

“…Histamine could profoundly affect the intestinal homeostasis through multiple pathways. It promotes increased vascular permeability and epithelial ion transport by acting on the H 1 receptors [30,31] and recruits neutrophils by acting on the H 4 receptors [32]. Forward et al demonstrated in vitro that histamine could attenuate the suppressor functions of CD4 + CD25 + T regulatory cells by acting on the H 1 receptors [33].…”

Lathyrus sativus diamine oxidase counteracts histamine‐induced cell proliferation, migration and pro‐angiogenic mediators release in human colon adenocarcinoma cell line Caco‐2

“…Although different signalling molecules have been identified, such as nitric oxide (NO), vascular endothelial growth factor (VEGF), prostaglandin, an increased histamine release is involved in gastrointestinal cancers (Kennedy, Hodges, Meng, Alpini, & Francis, 2012). In particular, histamine has been described as pivotal event involved in both aggravation of the severity of inflammatory bowel disease (Wechsler et al, 2018) and colon carcinogenesis and angiogenesis (Adams, Lawson, & Morris, 1994;Cianchi et al, 2005) through histamine receptor-2 (H2) activation (Tomita, Izumi, & Okabe, 2003), although its exact mechanism of action has not been fully understood.…”