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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.

Various heterotrimeric G(i) proteins are considered to be involved in cell migration and effector function of immune cells. The underlying mechanisms, how they control the activation of myeloid effector cells, are not well understood. To elucidate isoform-redundant and -specific roles for Gα(i) proteins in these processes, we analyzed mice genetically deficient in Gα(i2) or Gα(i3). First, we show an altered distribution of tissue macrophages and blood monocytes in the absence of Gα(i2) but not Gα(i3). Gα(i2)-deficient but not wild-type or Gα(i3)-deficient mice exhibited reduced recruitment of macrophages in experimental models of thioglycollate-induced peritonitis and LPS-triggered lung injury. In contrast, genetic ablation of Gα(i2) had no effect on Gα(i)-dependent peritoneal cytokine production in vitro and the phagocytosis-promoting function of the Gα(i)-coupled C5a anaphylatoxin receptor by liver macrophages in vivo. Interestingly, actin rearrangement and CCL2- and C5a anaphylatoxin receptor-induced chemotaxis but not macrophage CCR2 and C5a anaphylatoxin receptor expression were reduced in the specific absence of Gα(i2). Furthermore, knockdown of Gα(i2) caused decreased cell migration and motility of RAW 264.7 cells, which was rescued by transfection of Gα(i2) but not Gα(i3). These results indicate that Gα(i2), albeit redundant to Gα(i3) in some macrophage activation processes, clearly exhibits a Gα(i) isoform-specific role in the regulation of macrophage migration.