Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation

Abstract

Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7−/−) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7−/− mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7−/− mice and in mice reconstituted with bone marrow cells from 5-HT7−/− mice compared with control mice after DSS colitis. 5-HT7−/− mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

Serotonin receptor 5-HT7 regulates morphology and migratory properties of dendritic cells

“…In accordance with this hypothesis, a previous study reported a reduced ability of maturing Cdc42-deficient dendritic cells to upregulate CCR7 expression (Luckashenak et al, 2013). Furthermore, it has been demonstrated that 5-HT 7 R-mediated signaling regulates the activation of NF-κB in colon-derived dendritic cells (Kim et al, 2013). By contrast, inhibition of NF-κB has been shown to significantly reduce the induction of CCR7 expression in monocyte-derived dendritic cells (van de Laar et al, 2010).…”

Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis

“…Histological damage scoring of the colon was performed blindly on formalin-fixed, paraffin-embedded sections stained with H&E using previously described scoring criteria (20,51).…”

Distribution of 5-HT3, 5-HT4, and 5-HT7Receptors Along the Human Colon

“…5-HT 7 receptors are also found on macrophages and have been implicated as a potential target for treating intestinal inflammatory disorders. 59,60 Serotonin induces desensitization (tachyphylaxis) at different rates and magnitudes in different tissues and this is the case with 5-HT 4 receptor agonists as highlighted by prucalopride desensitizing pig atrium but not pig stomach 5-HT 4 receptors. 61 Different GRKs are associated with 5-HT 4 receptor desensitization depending on the tissue type in the rat and significantly these GRKs are not necessarily those predicted by studies using recombinant proteins expressed in cell culture.…”