In vivo Evidence for Partial Activation of Eosinophils via the Histamine H4-Receptor: Adoptive Transfer Experiments Using Eosinophils From H4R−/− and H4R+/+ Mice

Abstract

Our previous in vitro studies revealed that histamine via histamine the H4-receptors (H4R), as compared to other stimuli, such as eotaxin or formylpeptides, rather partially activates eosinophilic granulocytes (eosinophils). In order to evaluate the H4R-mediated activation of eosinophils in vivo, we employed dextran sodium sulfate (DSS)-induced colitis in mice, closely resembling human ulcerative colitis (UC), which is largely characterized by a local eosinophilic infiltration of the colon. IL-5-deficient BALB/c mice served as a model with reduced endogenous numbers of eosinophils, in which wild-type (H4R+/+) or H4R-deficient (H4R−/−) eosinophils were adoptively transferred during the course of DSS-induced colitis. During the 1-week observation period, transfer of eosinophils transiently reversed the acute clinical colitis-like phenotype (body weight loss, perianal bleeding, soft stool consistency) resulting from IL-5-deficiency. This reversion was significantly more pronounced upon transfer of eosinophils from H4R+/+ mice as compared to those from H4R−/− mice. Already at the end of the observation period, the clinical effects of the transfer of H4R+/+ and H4R−/− eosinophils became similar, as were the results of the histological examination of the cola and the analyses of cytokine production in cola and in re-stimulated lymph node cells performed at this time. Thus, analyzing clinical and pathological parameters representative of colitis in this model, we demonstrate that as well as in vitro, also in vivo histamine via the H4R only partially activates eosinophils.

Mouse Colonic Epithelial Cells Functionally Express the Histamine H4 Receptor

“…Lastly, this conclusion fits well to the pro-inflammatory function of the H 4 R in DSS-induced acute colitis in mice (Schirmer et al, 2015(Schirmer et al, , 2018. The H 4 R-mediated reduction of the epithelial barrier function may promote antigenic spread into the mucosal tissue and subsequently the granulocytic infiltration.…”

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H3 and H4 Receptors

“…191,192 The H 4 R is known to be mainly expressed in hematopoietic cells (e.g. dendritic cells, mast cells, eosinophils and T-lymphocytes) [193][194][195] , and also in colonic epithelial cells 196 and epidermal tissue (i.e. in keratinocytes in the prickle cell layer and granular layer of the epidermis 197 ).…”

Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

“…The increased number of mucosal mast cells able to release histamine has been shown to correlate with active colitis [28], as does the enhanced mucosal concentration of histamine [29]. A pro-inflammatory function of histamine and the H 4 R in DSS-induced colitis in mice has been demonstrated in previous studies [30][31][32][33]. Thus, in the present study, we aimed at analyzing whether the H 4 R bears a functional role in the pathogenesis of chemically induced CRC employing the AOM/DSS model in mice.…”