title: 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.
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Byram W
authors.initials: BW
authors.lastname: Bridle
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Ghia
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.forename: Shahzad N
authors.initials: SN
authors.lastname: Syed
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Manocha
authors.forename: Palanivel
authors.initials: P
authors.lastname: Rengasamy
authors.forename: Mohammad Sharif
authors.initials: MS
authors.lastname: Shajib
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
authors.forename: Peter B
authors.initials: PB
authors.lastname: Hedlund
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011985:Receptors, Serotonin / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001557:Benzenesulfonates; D016328:NF-kappa B; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; C007488:dinitrobenzenesulfonic acid; D016264:Dextran Sulfate