5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo

Müller, Tobias; Dürk, Thorsten; Blumenthal, Britta; Grimm, Melanie; Cicko, Sanja; Panther, Elisabeth; Sorichter, Stephan; Herouy, Yared; Virgilio, Francesco Di; Ferrari, Davide; Norgauer, Johannes; Idzko, Marco

doi:10.1371/journal.pone.0006453

Cited by 144 publications

(116 citation statements)

References 46 publications

(64 reference statements)

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“…Because 5-HT 7 receptor expression has been shown to be more prominent on mature DCs (34), it can be reasoned that 5-HT-induced modulation of cytokine release is dependent on the differentiation stage of DCs, and 5-HT 7 receptormediated influence on cytokine secretion is maturation dependent. Similar effects of 5-HT on cytokine secretion have been observed in monocyte-derived DCs (70). We found that addition of LPS to CD11c + colonic DC culture did not significantly upregulate IL-12p40, IL-6, and TNF-a with or without 5-HT stimulation.…”

Section: Cd11csupporting

confidence: 84%

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

109

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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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Section: Cd11csupporting

confidence: 84%

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

109

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“…Serotonin directly modulates functions of several other immune cells, but unlike in the case of dendritic cells, mast cells, and eosinophils, serotonin did not act as a chemoattractant to induce in vitro migration of neutrophils. 7,[41][42][43][44] In vitro plateletneutrophil rosetting was also independent of the platelet serotonin content, indicating that serotonin does not influence platelet P-selectin expression and platelet-neutrophil interactions. It is more probable that serotonin enhances neutrophil extravasation by regulating endothelial selectin expression, because serotonin induces WPB exocytosis in cultured endothelial cells 10,11 and injection of serotonin enhanced leukocyte rolling in the Tph1 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 95%

Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

Duerschmied

Suidan

Demers

et al. 2013

Blood

Self Cite

266

231

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Key Points• During inflammation, serotonin released by platelets activates vessel wall promoting leukocyte adhesion and recruitment.• Absence of platelet serotonin improves survival after lipopolysaccharide-induced endotoxic shock.The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1-deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1 ؊/؊ mice. The velocity of rolling leukocytes was higher in Tph1 ؊/؊ mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1 ؊/؊ mice. Diminished rolling in Tph1 ؊/؊ mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1 ؊/؊ mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1 ؊/؊ mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity. (Blood. 2013;121(6):1008-1015) IntroductionPlatelets store serotonin in their dense granules at millimolar concentration and secrete it when they become activated. 1,2 This requires a complex mechanism of uptake, storage, and targeted release that is similar to that in neurons, with the exception that platelets are not stationary but circulate in high numbers throughout the vasculature. Platelets do not synthesize serotonin but incorporate and store serotonin that is synthesized in duodenal enterochromaffin cells and secreted into blood. Several different effects of non-neuronal serotonin have been unraveled in the past, including prohemostatic (on platelets and vascular smooth muscle cells), 3,4 mitogenic (on hepatocytes and pulmonary smooth muscle cells), 5,6 and immunomodulatory (on lymphocytes, monocytes, and smooth muscle cells) 7-9 functions. In vitro studies have shown that serotonin also activates the release of Weibel-Palade bodies (WPBs) from endothelial cells, which would promote leukocyte rolling via the WPB constituent P-selectin. 10,11 However, it is not clear whether serotonin influences neutrophil-endothelial interactions, a central step in early innate immune responses.We chose 2 approaches to study serotonin effects on leukocyte rolling and recruitment: genetic defi...

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“…Human monocytes release different cytokines and chemokines, mainly via 5-HT 3 , 5-HT 4 and 5-HT 7 activation (35). Past studies also showed that 5-HT increase production of the pro-inflammatory cytokine IL-6 in mature Dendritic cells (DCs) via 5-HT 3 , 5-HT 4 and 5-HT 7 (8,9). And DCs are known to produce different chemokines thereby regulating the traffic of Th1 and Th2 cells into inflamed tissue (36).…”

Section: Discussionmentioning

confidence: 99%

“…More than 90% of 5-HT in the body is secreted from EC cells which are located within the mucosal mucosa, and the tryptophan hydroxylase (TPH) which in EC cells is the rate-limiting enzyme in the 5-HT synthesis process (5)(6)(7). Moreover, recent studies indicated that CD4 + T cells played an important role in the development of colonic EC cell hyperplasia in intestinal infection, and EC cells were influenced by helper T-cell subtype 1 (Th1) or subtype 2 (Th2) cytokine predominant environments (8,9). Cynaropicrin ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Analgesic activity of cynaropicrinon on post‑inflammatory irritable bowel syndrome visceral hypersensitivity in a rat model

et al. 2017

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Abstract. Visceral hypersensitivity is one of the most common symptoms in patients with post-inflammatory-irritable bowel syndrome (PI-IBS). Enterochromaffin (EC) cells and 5-hydroxytryptamine (5-HT) are important in the development of visceral hyperalgesia, and EC cells are influenced by helper T-cell subtype 1 or 2 cytokine predominant environments. In the present study, the analgesic effect of cynaropicrin and its underlying mechanism on the treatment of trinitrobenzene sulfonic (TNBS)-induced PI-IBS visceral hyperalgesia rats was investigated. The results from the abdominal withdrawal reflex tests and electromyography recordings indicated that treatment with cynaropicrin significantly and dose-dependently alleviated the visceral hyperalgesia of PI-IBS rats (P<0.05). In addition, the increased colonic 5-HT content, colonic tryptophan hydroxylase expression, EC cell number and the cytokine levels, including tumor necrosis factor-α and interleukin-6 in PI-IBS rats were significantly alleviated by cynaropicrin (P<0.05). These data demonstrate that the analgesic activity of cynaropicrin on TNBS-induced PI-IBS visceral hypersensitive rats was mediated via reduction of cytokines levels. Thus, cynaropicrin as a bioactive natural product may offer promising therapeutic avenues for visceral hypersensitivity in IBS.

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5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo

Cited by 144 publications

References 46 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

Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

Analgesic activity of cynaropicrinon on post‑inflammatory irritable bowel syndrome visceral hypersensitivity in a rat model

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