Abstract
Inflammatory bowel diseases (IBD) are a growing health problem worldwide, severely affecting patients’ life qualities and life expectancies. Therapeutic options, which are rare and focus on symptoms associated with the disease, suffer from increasing numbers of patients refractory to the established strategies. Thus, in order to generate new therapeutic regimens, the detailed understanding of the pathogenic mechanisms causing IBD is necessary. Histamine is an inflammatory mediator associated with IBD. Four histamine receptors are currently known of which the histamine H4-receptor (H4R) has been shown to possess a pro-inflammatory function in several experimental models of inflammatory diseases, including dextran sodium sulfate (DSS)-induced colitis in mice. No single model reflects the complexity of human IBD, but each model provides valuable information on specific aspects of IBD pathogenesis. While DSS-induced colitis mostly relies on innate immune mechanisms, trinitrobenzene sulfonic acid (TNBS)-induced colitis rather reflects T-cell mechanisms. Consequently, an observation made in a single model has to be verified in at least one other model. Therefore, in the present study we investigated the effect of genetic blockade of H4R-signaling in mice subjected to the model of TNBS-induced acute colitis. We analyzed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colon and local cytokine production. Genetic ablation of H4R expression worsened clinical signs of acute colitis and histological appearance of colon inflammation after TNBS application. Moreover, TNBS instillation enhanced local synthesis of inflammatory mediators associated with a neutrophilic response, i.e., CXCL1, CXCL2, and interleukin-6. Lastly, also myeloperoxidase concentration, indicative for the presence of neutrophils, was elevated in cola of TNBS-treated mice due to the absence of H4R expression. Our results indicate an anti-inflammatory role of histamine via H4R in TNBS-induced acute neutrophilic colitis in mice, thus questioning the strategy of pharmacological H4R blocked as new therapeutic option for patients suffering from IBD.
Highlights
Inflammatory bowel diseases (IBD) are a global health concern with growing incidence, especially in industrialized countries (Molodecky et al, 2012)
In H4R−/− mice, the symptoms induced by 2 mg/mouse TNBS were significantly more severe as compared to those observed in WT mice
Anatomical parameters support the notion that lack of H4R supports TNBS-induced colitis: while in WT mice experimentally induced colitis does not lead to a reduction of the colon length, in H4R−/− mice it is significantly reduced after TNBS treatment as compared to EtOH/PBS treatment (Figure 1C)
Summary
Inflammatory bowel diseases (IBD) are a global health concern with growing incidence, especially in industrialized countries (Molodecky et al, 2012). There are mainly two clinical entities of IBD, namely ulcerative colitis (UC) and Crohn’s disease (CD), both characterized by chronic, relapsing inflammatory conditions in the gastrointestinal tract These two manifestations of IBD differ in their clinical and histopathological presentation and, from an immunological point of view, in the association of CD and UC with a dysregulation of a Th1-type or a Th2type immune response, respectively (Geremia et al, 2014). There are several different rodent models existing in order to mimic specific features of human IBD Because of their relative simplicity, easy establishment, low costs and good reproducibility, chemically induced colitis models are currently the most widely used models of IBD (Wirtz et al, 2007). TNBSinduced colitis has been reported to focus on pathophysiologic aspects of the adaptive immune response, whereas DSS-induced colitis causes more of a dysregulation of the innate immune response (Wirtz et al, 2007)
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