Serotonin Has a Key Role in Pathogenesis of Experimental Colitis

Ghia, Jean–Eric; Li, Nan; Wang, Huaqing; Collins, Matthew A.; Deng, Yikang; El–Sharkawy, Rami T.; Côté, Francine; Mallet, Jacques; Khan, Waliul I.

doi:10.1053/j.gastro.2009.08.041

Cited by 326 publications

(365 citation statements)

References 36 publications

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“…A proinflammatory role for 5-HT has also been demonstrated in other studies where chemicalinduced colitis or spontaneous colitis associated with an IL-10 deficiency is increased in severity when coupled with the 5-HTenhancing effects of a knockout of the serotonin reuptake transporter, SERT (25,26). We have also shown that 5-HT plays a key role in the activation of immune cells to produce proinflammatory cytokines (24,27). Taken together, these findings suggest 5-HT as an important molecule in the activation of immune cells and in the pathogenesis of colitis.…”

mentioning

confidence: 51%

“…EC cells are located in very close proximity to or in contact with key immune cells (23); thus, it is very likely that 5-HT plays an important role in immune activation and generation of gut inflammation in various GI disorders including IBD. Recently, we have shown that TPH1-deficient (TPH1 2/2 ) mice, which have significantly lower amounts of 5-HT in the gut, exhibit reduced severity of colitis in two different models of experimental colitis (induced by dextran sulfate sodium [DSS] and dinitrobenzene sulfonic acid [DNBS]), whereas replenishing 5-HT levels upregulated colitis severity (24). A proinflammatory role for 5-HT has also been demonstrated in other studies where chemicalinduced colitis or spontaneous colitis associated with an IL-10 deficiency is increased in severity when coupled with the 5-HTenhancing effects of a knockout of the serotonin reuptake transporter, SERT (25,26).…”

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confidence: 99%

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

Kim

Bridle

Ghia

et al. 2013

The Journal of Immunology

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114

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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.

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confidence: 51%

mentioning

confidence: 99%

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

Kim

Bridle

Ghia

et al. 2013

The Journal of Immunology

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114

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“…However, these metabolites have been reported rather cofactors in the oxidative damage (12,13). Another metabolite, 5-hydrotryptamine (5-HT), was reported to be involved in the pathogenesis of inflammation in experimental colitis (14). Moreover, 5-HT have been reported to accelerate NO production via endothelial NOS (eNOS) in vitro (15).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis

Shizuma¹,

Mori²,

Fukuyama³

2009

Turk J Gastroenterol

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“…46 To address the role of 5-HT in immune activation and regulation of gut inflammation, Ghia et al studied Tph1 KO mice and hypothesized that 5-HT activates and promotes survival of immune cells. 47 Using different models of colitis, they observed a delayed onset and decreased severity of clinical disease together with lower macroscopic and histological damage scores in Tph1−/− mice and mice treated with parachlorophenylalanine (PCPA; an inhibitor of Tph activity), as compared to WT mice after induction of colitis. Along with a down-regulation of macrophage infiltration, they observed a decreased production of pro-inflammatory cytokines.…”

Section: ■ Tph1-derived Serotonin In the Gut: What Does It Really Do?mentioning

confidence: 99%

Life without Peripheral Serotonin: Insights from Tryptophan Hydroxylase 1 Knockout Mice Reveal the Existence of Paracrine/Autocrine Serotonergic Networks

Amireault

Sibon

Côté

2012

ACS Chem. Neurosci.

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138

113

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Since its identification, 75 years ago, the monoamine serotonin (5-HT) has attracted considerable attention toward its role as a neurotransmitter in the central nervous system. Yet, increasing evidence, from a growing number of research groups, substantiates the fact that 5-HT regulates important nonneuronal functions. Peripheral 5-HT, synthesized by the enzyme tryptophan hydroxyase (Tph) in intestinal cells, was assumed to be distributed throughout the entire body by blood platelets and to behave as a pleiotropic hormone. A decade ago, generation of a mouse model devoid of peripheral 5-HT lead to the discovery of a second isoform of the enzyme Tph and also suggested that 5-HT might act as a local regulator in various organs. The objective of this review is to highlight the newly discovered functions played by the monoamine using the Tph1 KO murine model and to outline current findings that led to the discovery of complete serotonergic systems in unexpected organs. Within an organ, both the presence of local Tph enzymatic activity and serotonergic components are of particular importance as they support the view that 5-HT meets the criteria to be qualified as a monoamine with a paracrine/autocrine function.

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Serotonin Has a Key Role in Pathogenesis of Experimental Colitis

Cited by 326 publications

References 36 publications

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

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

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis

Life without Peripheral Serotonin: Insights from Tryptophan Hydroxylase 1 Knockout Mice Reveal the Existence of Paracrine/Autocrine Serotonergic Networks

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