Abstract
Mucosal inflammation in the gut is characterized by infiltration of innate and adaptive immune cells and by an alteration in serotonin-producing enterochromaffin cells. We investigated the role of serotonin in the function of dendritic cells (DCs) and sequential T-cell activation in relation to generation of gut inflammation. DCs isolated from tryptophan hydroxylase-1-deficient (TPH1(-/-)) mice, which have reduced serotonin in the gut, and wild-type (TPH1(+/+)) mice with or without dextran sulfate sodium (DSS)-induced colitis were stimulated with lipopolysaccharide to assess interleukin-12 (IL-12) production. Isolated DCs from TPH1(+/+) and TPH1(-/-) mice were also cocultured with CD4(+) T cells of naive TPH1(+/+) mice to assess the role of serotonin in priming T cells. In addition, serotonin-pulsed DCs were transferred to TPH1(-/-) mice to assess the effect on DSS-induced colitis. Consistent with a reduced severity of colitis, DCs from DSS-induced TPH1(-/-) mice produced less IL-12 compared with the TPH1(+/+) mice. In vitro serotonin stimulation restored the cytokine production from TPH1(-/-) DCs and adoptive transfer of serotonin-pulsed DCs into TPH1(-/-) up-regulated colitis. Furthermore, CD4(+) T cells primed by TPH1(-/-) DCs produce reduced the levels of IL-17 and interferon-γ. This study provides novel information on serotonin-mediated immune signaling and promotion of interactions between innate and adaptive immune responses in the context of gut inflammation, which may ultimately lead to improved strategies to combat gut inflammatory disorders.
Highlights
Inflammation in the gastrointestinal (GI) tract is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems
Using tryptophan hydroxylase-1– deficient (TPH1Ϫ/Ϫ) mice, which have significantly reduced amounts of serotonin in the gut, and mice treated with the serotonin synthesis inhibitor para-chloro-D, L-phenylalanine (PCPA), we demonstrated a critical role of serotonin in the generation of colitis in two different models of colitis [dextran sulfate sodium (DSS) and dinitrobenzene sulfonic acid (DNBS)]
Dendritic cells (DCs) are critical in the production of IL-12p40 in many immune responses, including those associated with inflammatory bowel disease (IBD)
Summary
Inflammation in the gastrointestinal (GI) tract is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. Because of the strategic location of EC cells in gut mucosa, it is likely that serotonin plays an important role in immune activation in relation to gut pathology and pathophysiology in various GI disorders, including IBD. The character of a T-cell (key player in adaptive immune system) response, whether effector T cells (TH1, TH2, TH17) or regulatory T cells (Tr, TH3), reflects instruction by the initiating DCs. Studies on human DCs revealed the presence of different serotoninergic receptors on DCs, and functional studies indicated that activation of serotonin 4 and serotonin 7 receptor enhanced the release of the cytokines interleukin-1 (IL1) and IL-8.18 DCs expressing serotonin receptors are situated close to EC cells, and are considered to play an important role in immune activation and generation of intestinal inflammation, the role of serotonin in modulating DC function in the context of intestinal inflammation remains to be determined. In this study we investigated the role of serotonin in the function of DCs and sequential T-cell activation in relation to generation of gut inflammation in a well-defined experimental model of colitis
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