Novel 5-HT7 receptor antagonists modulate intestinal immune responses and reduce severity of colitis

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 327; no. 1; p. G57
• Main Authors: Kwon, Yun Han, Blass, Benjamin E, Wang, Huaqing, Grondin, Jensine A, Banskota, Suhrid, Korzekwa, Kenneth, Ye, Min, Gordon, John C, Colussi, Dennis, Blattner, Kevin M, Canney, Daniel J, Khan, Waliul I
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2024
• Subjects: Ablation; Animal models; CD4 antigen; CD45RB antigen; Crohn's disease; Dextran; Dextran sulfate; Dextrans; In vivo methods and tests; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Lymphocytes; Lymphocytes T; Receptors; Serotonin; Serotonin S7 receptors; Therapeutic targets; Ulcerative colitis; 5-HT7 receptor; Colitis; Inflammatory Bowel Disease; Serotonin; 5-HT
• ISSN: 1040-0605; 0193-1857; 1522-1547; 1522-1547; 1522-1504
• DOI: 10.1152/ajpgi.00299.2023

Inflammatory bowel disease (IBD) encompasses a number of debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation and is associated with altered serotonin (5-hydroxytryptamine; 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT ) is one of the most recently discovered. We previously reported that blocking 5-HT signaling, with either a selective 5-HT receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely MC-170073 and MC-230078, which target 5-HT receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by utilizing dextran sulfate sodium (DSS) and the transfer of CD4+CD45RB T cells to induce intestinal inflammation. Inhibition of 5-HT receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of pro-inflammatory cytokines in comparison to vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT is a viable therapeutic target for IBD.