Serotonin 5-HT7 Receptor Is Critically Involved in Acute and Chronic Inflammation of the Gastrointestinal Tract

Guseva, Daria; Holst, Katrin; Kaune, Beate; Meier, Martin; Keubler, Lydia M.; Glage, Silke; Büettner, Manuela; Bleich, André; Pabst, Oliver; Bachmann, Oliver; Ponimaskin, Evgeni

doi:10.1097/mib.0000000000000150

Cited by 65 publications

(76 citation statements)

References 54 publications

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“…Unfortunately, as compelling as this idea seems to be, strong evidence has been advanced for an equally compelling but contrary hypothesis. Both sides of the argument agree that dendritic cells in the intestine express the 5-HT 7 receptor; however, the contrary evidence suggests that the dendritic cell 5-HT 7 receptor is anti-inflammatory, not proinflammatory [94]. A 5-HT 7 antagonist, SB-269970, and the deletion of 5-HT 7 receptors were found to increase the severity of inflammation, and stimulation of the 5-HT 7 receptor exerted anti-inflammatory effects.…”

Section: Serotoninmentioning

confidence: 99%

“…A 5-HT 7 antagonist, SB-269970, and the deletion of 5-HT 7 receptors were found to increase the severity of inflammation, and stimulation of the 5-HT 7 receptor exerted anti-inflammatory effects. A difference between the studies is that the proinflammatory side [93] employed a dose of SB-269970 that was 2500-fold higher than that utilized by the anti-inflammatory advocates [94]. Conceivably, the higher dose of SB-269970 exerted non-specific effects.…”

Section: Serotoninmentioning

confidence: 99%

“…A phenomenon of this type could therefore contribute to the pathogenesis of IBD and/or to the severity of GI symptoms. One interesting observation is that, during experimental inflammation in mice and in human patients with IBD, there is a strong upregulation of 5-HT 7 receptor-expressing dendritic cells in the lamina propria [94]. Whether the stimulation of these receptors is driving inflammation or modulating it, however, cannot be determined until the above-discussed conflict over the effect of 5-HT 7 stimulation of dendritic cells is resolved.…”

Section: Serotoninmentioning

confidence: 99%

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Enteric Neuronal Regulation of Intestinal Inflammation

Margolis

Gershon

2016

Trends in Neurosciences

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Recent research has highlighted the importance of the two-way interaction between the nervous and immune systems. This interaction is particularly important in the bowel because of the unique properties of this organ. The lumen of the gut is lined by a very large but remarkably thin surface that separates the body from the enteric microbiome. Immune defenses against microbial invasion are thus well developed, and neuroimmune interactions are important in regulating and integrating these defenses. Important concepts in the phylogeny of neuroimmunity, enteric neuronal and glial regulation of immunity, changes that occur in the enteric nervous system during inflammation, the fundamental role of serotonin (5-HT) in enteric neuroimmune mechanisms, and future perspectives are reviewed.

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Section: Serotoninmentioning

confidence: 99%

Section: Serotoninmentioning

confidence: 99%

Section: Serotoninmentioning

confidence: 99%

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Enteric Neuronal Regulation of Intestinal Inflammation

Margolis

Gershon

2016

Trends in Neurosciences

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“…The mammalian intestinal tract is the largest immune organ in the body and is composed of several different types of cells [29]. 5-HT serves as a link between the gut and immune regulation [30, 31]. This suggests that 5-HT may be involved in the nervous system-mediated regulation of the digestion-immune system interface.…”

Section: Discussionmentioning

confidence: 99%

Role of serotonin on the intestinal mucosal immune response to stress-induced diarrhea in weaning mice

et al. 2017

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BackgroundDuring weaning, babies and young animal often experience diarrhea from food intolerance and/or decreasing levels of maternal antibodies, and diarrhea tends to be particularly severe during the early-weaned period, which often exhibits an underdeveloped immune system, a disturbed gut environment and results in nutrient malabsorption and dehydration. It was deduced that neuroendocrine might have close relation with diarrhea, especially 5-HT.MethodsTo explore the role of serotonin (5-HT) in weaning mice subjected to stress-induced diarrhea, 21-day-old weaned mice were divided into the following groups: control group, stress-induced diarrhea group (restrained by binding the hind limbs and intragastric administration of folium sennae with 0.4 g/mL, 15 mL/kg body weight) and para-chlorophenylalanine (PCPA) + stress-induced diarrhea group (30 mg/mL, 300 mg/kg body weight PCPA intraperitoneal injection before stress-induced diarrhea treatment).ResultsBased on results from enzyme-linked immunosorbent assays, histological staining, lymphocyte proliferation assays and flow cytometry analysis, we found that the mice experienced increases in several stress markers, which coincided with severe diarrhea and an increase in 5-HT levels. However, pre-treatment with PCPA resulted in a decrease in the stress indicators and the severity of diarrhea, which correlated with decreased 5-HT levels. Interestingly, stress-induced diarrhea caused changes in various aspects of the immune system, including the amount of intraepithelium lymphocytes, CD4+/CD8+ T lymphocyte populations, B and T lymphocyte proliferation, and the secretion of sIgA and cytokines in the small intestine and ileum. However, these immune system changes could be reversed upon treatment with PCPA.ConclusionsWe observed a distinct correlation between 5-HT levels and the occurrence of stress-induced diarrhea in weaning mice, which may result in the deregulation of the mucosal immune system.

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“…In this context, recent works have shown that 5-HT [5], 5-HT receptors [6] and SERT [7] would play a chief role in the development of IBD. In fact, recent studies have suggested that modifications of the activity of selective serotonin receptors and reuptake transporter in the gut could be effective for controlling IBD activity and associated symptoms [8,9].…”

Section: Introductionmentioning

confidence: 99%

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.

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Serotonin 5-HT7 Receptor Is Critically Involved in Acute and Chronic Inflammation of the Gastrointestinal Tract

Abstract: The 5-HT7R expressed on CD11c/CD86-positive myeloid cells modulates the severity of intestinal inflammation in an acute and chronic colitis and thus represents a potential therapeutic target for the treatment of inflammatory disorders such as CD.

Cited by 65 publications

References 54 publications

Enteric Neuronal Regulation of Intestinal Inflammation

Enteric Neuronal Regulation of Intestinal Inflammation

Role of serotonin on the intestinal mucosal immune response to stress-induced diarrhea in weaning mice

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

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