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. 2024 Jul 1;327(1):G57-G69.
doi: 10.1152/ajpgi.00299.2023. Epub 2024 May 7.

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

Yun Han Kwon  1   2 , Benjamin E Blass  3 , Huaqing Wang  1   2 , Jensine A Grondin  1   2 , Suhrid Banskota  1   2 , Kenneth Korzekwa  3 , Min Ye  3 , John C Gordon  3 , Dennis Colussi  3 , Kevin M Blattner  3 , Daniel J Canney  3 , Waliul I Khan  1   2
Affiliations

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

Yun Han Kwon et al. Am J Physiol Gastrointest Liver Physiol. .

Abstract

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 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-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 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-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 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 proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 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-HT7 is a viable therapeutic target for IBD.NEW & NOTEWORTHY This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease.

Keywords: 5-HT; 5-HT7 receptor; 5-HT7 receptor antagonist; inflammatory bowel disease; serotonin.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

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Graphical abstract
Figure 1.
Figure 1.
Structure of MC-170073.
Figure 2.
Figure 2.
Administration of 5-HT7 antagonist (MC-170073) attenuates the severity of acute DSS-induced colitis. In an acute model of colitis, C57BL/6 mice were treated once daily with MC-170073 (10 mg/kg ip) for 6 days starting 1 day before the beginning of the 5-day period of 4% DSS. A: disease activity index (DAI). B: macroscopic score. C: histological score. D: representative images of hematoxylin-eosin (H&E)-stained colon sections. E: colonic MPO level. F: colonic IL-1β levels. G: colonic IL-6 levels. H: colonic TNF-α levels. Each symbol represents an individual mouse. Data are represented as means ± SE from 4 to 8 mice per group. Statistical significance was determined by one-way analysis of variance (ANOVA) with Bonferroni multiple comparison. *P < 0.05 compared with vehicle. #P < 0.05 compared with DSS. DSS, dextran sulfate sodium; MPO, myeloperoxidase; 5-HT7, 5-hydroxytryptamine receptor type 7.
Figure 3.
Figure 3.
Administration of 5-HT7 antagonist (MC-170073) attenuates the severity of chronic DSS-induced colitis. In a chronic model of colitis, C57BL/6 mice were subjected to three cycles of DSS and, during the last cycle of DSS, were treated with MC-170073 (10 mg/kg ip). A: macroscopic score. B: representative images of hematoxylin-eosin (H&E)-stained colon sections. C: histological score. D: colonic MPO level. E: colonic IL-1β levels. F: colonic TNF-α levels. Each symbol represents an individual mouse. Data are represented as means ± SE from 4 to 7 mice per group. Statistical significance was determined by one-way analysis of variance (ANOVA) with Bonferroni multiple comparisons. *P < 0.05 compared with vehicle. DSS, dextran sulfate sodium; MPO, myeloperoxidase; 5-HT7, 5-hydroxytryptamine receptor type 7.
Figure 4.
Figure 4.
Structure of enantiomers MC-230078 and MC-230079.
Figure 5.
Figure 5.
Administration of 5-HT7 antagonist (MC-230078) attenuates the severity of DSS-induced colitis. MC-230078 at 10 mg·kg−1 body weight was orally administered twice daily starting from day 0 of 5% DSS for 5 days. A: body weight change. B: disease activity index (DAI). C: macroscopic score. D: representative images of hematoxylin-eosin (H&E)-stained colon sections. E: histological score. F: colonic MPO level. G: colonic IL-1β level. Each symbol represents an individual mouse. Data are represented as means ± SE from 6 mice per group. Statistical significance was determined by unpaired Student’s t test. *P < 0.05 compared with DSS. DSS, dextran sulfate sodium; MPO, myeloperoxidase; 5-HT7, 5-hydroxytryptamine receptor type 7.
Figure 6.
Figure 6.
Administration of 10 mg/kg of 5-HT7 antagonist (MC-230078) alleviates the development of CD45RBhigh T cell-induced colitis. A: experimental design. Briefly, Rag1−/− (C57BL/6J background) mice were reconstituted with FACS-sorted 5.0 × 105 CD4+CD45RBhi T cells harvested from the spleen of healthy C57BL/6J mice. At week 6, either vehicle or MC-230078 (5 or 10 mg·kg−1 body wt) was orally administered twice daily for 10 days before euthanization. B: body weight change. C: disease activity index (DAI). D: macroscopic score. E: representative images of hematoxylin-eosin (H&E)-stained colon sections. F: histological score. Each symbol represents an individual mouse. Data are represented as means ± SE from 5 to 9 mice per group. *P < 0.05 compared with no transfer. #P < 0.05, compared with vehicle. Statistical significance was determined by unpaired Student’s t test, one-way or two-way analysis of variance (ANOVA) with Bonferroni multiple comparisons. 5-HT7, 5-hydroxytryptamine receptor type 7.
Figure 7.
Figure 7.
5-HT7 antagonist (MC-230078) at 10 mg/kg reduces the production of MPO and proinflammatory cytokines in a CD45RBhigh T cell-induced colitis. A: colonic 5-HT level. B: colonic MPO level. C–G: levels of colon proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ, and IL-17A). Each symbol represents an individual mouse. Data are represented as means ± SE from 5 to 9 mice per group. Statistical significance was determined by one-way analysis of variance (ANOVA) with Bonferroni multiple comparison. *P < 0.05 compared with no transfer. #P < 0.05 compared with vehicle. MPO, myeloperoxidase; 5-HT7; 5-hydroxytryptamine receptor type 7.
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