Mouse Colonic Epithelial Cells Functionally Express the Histamine H Receptor.

We hypothesized that, in mice, histamine via the histamine receptor subtype 4 (HR) on colon epithelial cells affects epithelial barrier integrity, perturbing physiologic function of the colonic mucosa and thus aggravating the severity of colitis. To test this hypothesis, bone marrow-chimeric mice were generated from HR knockout (HR) and wild-type (WT) BALB/cJ mice and subjected to the dextrane sodium sulfate (DSS)-induced acute colitis model. Clinical symptoms and pathohistological derangements were scored. Additionally, total RNA was extracted from either mouse whole-colon homogenates or primary cell preparations enriched for epithelial cells, and gene expression was analyzed by real-time quantitative polymerase chain reaction. The impact of the HR on epithelial barrier function was assessed by measurement of transepithelial electrical resistence of organoid-derived two-dimensional monolayers from HR and WT mice using chopstick electrodes. Bone marrow-chimeric mice with genetic depletion of the HR in nonhematopoietic cells exhibited less severe DSS-induced acute colitis symptoms compared with WT mice, indicating a functional proinflammatory expression of HR in nonimmune cells of the colon. Analysis of HR expression revealed the presence of HR mRNA in colon epithelial cells. This expression could be confirmed and complemented by functional analyses in organoid-derived epithelial cell monolayers. Thus, we conclude that the HR is functionally expressed in mouse colon epithelial cells, potentially modulating mucosal barrier integrity and intestinal inflammatory reactions, as was demonstrated in the DSS-induced colitis model, in which presence of the HR on nonhematopoietic cells aggravated the inflammatory phenotype. SIGNIFICANCE STATEMENT: The histamine H receptor (HR) is functionally expressed on mouse colon epithelial cells, thereby aggravating dextrane sodium sulfate-induced colitis in BALB/cJ mice. Histamine via the HR reduces transepithelial electrical resistance of colon epithelial monolayers, indicating a function of HR in regulation of epithelial barrier integrity.