Serotonin Activates Dendritic Cell Function in the Context of Gut Inflammation

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. 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. Inflammation in the gastrointestinal (GI) tract is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in serotonin producing enterochromaffin (EC) cells. EC cells are the most well-characterized subset of GI endocrine cells, which are dispersed throughout the GI mucosa and are the main source of serotonin in the gut.1Gershon M.D. Serotonin and its implication for the management of irritable bowel syndrome.Rev Gastroenterol Disord. 2003; 3: S25-S34Google Scholar, 2Ham T.S. Regional distribution and relative frequency of gastrointestinal endocrine cells in large intestines of C57BL/6 mice.J Vet Sci. 2002; 3: 233-238Crossref PubMed Scopus (9) Google Scholar, 3Khan W.I. Ghia J.E. Gut hormones: emerging role in immune activation and inflammation.Clin Exp Immunol. 2010; 161: 19-27Crossref PubMed Scopus (146) Google Scholar, 4Kim D.Y. Camilleri M. Serotonin: a mediator of the brain-gut connection.Am J Gastroenterol. 2000; 95: 2698-2709Crossref PubMed Scopus (398) Google Scholar Serotonin is an important enteric mucosal signaling molecule that influences gut physiology (motor and secretory function) after inflammation and is considered important in gut function. Changes in intestinal EC cell numbers and serotonin levels are observed in patients with inflammatory bowel disease (IBD)5Ahonen A. Kyosola K. Penttila O. Enterochromaffin cells in macrophages in ulcerative colitis and irritable colon.Ann Clin Res. 1976; 8: 1-7PubMed Google Scholar, 6Belai A. 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Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G207-G216Crossref PubMed Scopus (253) Google Scholar In addition, an alteration in the number of EC cells and in serotonin level is observed in enteric infection–induced inflammation in the gut10Grondahl M.L. Jensen G.M. Nielsen C.G. Skadhauge E. Olsen J.E. Hansen M.B. Secretory pathways in Salmonella typhimurium–induced fluid accumulation in the porcine small intestine.J Med Microbiol. 1998; 47: 151-157Crossref PubMed Scopus (40) Google Scholar, 11Kordasti S. Sjovall H. Lundgren O. Svensson L. Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea.Gut. 2004; 53: 952-957Crossref PubMed Scopus (69) Google Scholar, 12O'Hara J.R. Skinn A.C. MacNaughton W.K. Sherman P.M. Sharkey K.A. Consequences of Citrobacter rodentium infection on enteroendocrine cells and the enteric nervous system in the mouse colon.Cell Microbiol. 2006; 8: 646-660Crossref PubMed Scopus (63) Google Scholar, 13Wang H. Steeds J. Motomura Y. Deng Y. Verma-Gandhu M. El-Sharkawy R.T. McLaughlin J.T. Grencis R.K. Khan W.I. CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection.Gut. 2007; 56: 949-957Crossref PubMed Scopus (105) Google Scholar and functional disorders such as irritable bowel syndrome (IBS).7Coates M.D. Mahoney C.R. Linden D.R. Sampson J.E. Chen J. Blaszyk H. Crowell M.D. Sharkey K.A. Gershon M.D. Mawe G.M. Moses P.L. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1664Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar, 14Camilleri M. Northcutt A.R. Kong S. Dukes G.E. McSorley D. Mangel A.W. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.Lancet. 2000; 355: 1035-1040Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar The association between alteration in EC cell numbers and serotonin production and various GI diseases highly emphasizes the significance of serotonin in intestinal homeostasis. 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. EC cells synthesize serotonin from its precursor l-tryptophan. Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of serotonin from tryptophan and has been detected prominently in EC cells.15Fitzpatrick P.F. Tetrahydropterin-dependent amino acid hydroxylases.Annu Rev Biochem. 1999; 68: 355-381Crossref PubMed Scopus (432) Google Scholar Recent studies show that there are two isoforms of TPH enzymes that regulate the serotonin system. TPH1 is mainly present in peripheral organs, such as the EC cells and spleen, whereas TPH2 predominates in the brainstem and myenteric plexus neurons.16Walther D.J. Bader M. A unique central tryptophan hydroxylase isoform.Biochem Pharmacol. 2003; 66: 1673-1680Crossref PubMed Scopus (571) Google Scholar, 17Walther D.J. Peter J.U. Bashammakh S. Hortnagl H. Voits M. Fink H. Bader M. Synthesis of serotonin by a second tryptophan hydroxylase isoform.Science. 2003; 299: 76Crossref PubMed Scopus (1224) Google Scholar Recently, using tryptophan hydroxylase-1–deficient (TPH1−/−) 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)].8Ghia J.E. Li N. Wang H. Collins M. Deng Y. El-Sharkawy R.T. Cote F. Mallet J. Khan W.I. Serotonin has a key role in pathogenesis of experimental colitis.Gastroenterology. 2009; 137: 1649-1660Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar Decreased severity of colitis and down-regulation of proinflammatory cytokine production were observed in TPH1−/− mice compared with wild-type mice and in PCPA-treated mice after induction of colitis. Dendritic cells (DCs) are important innate immune cells and perform a key role in activation of immune response. DCs are the major source of proinflammatory mediators, including cytokines, reactive oxygen, and nitrogen intermediates, and play a critical role in the generation of inflammation in the intestinal tract. 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-1β (IL-1β) and IL-8.18Idzko M. Panther E. Stratz C. Muller T. Bayer H. Zissel G. T. S. F. M. Y. J. D. The serotoninergic receptors of human dendritic and to cytokine Immunol. 2004; PubMed Scopus Google Scholar DCs serotonin receptors are to EC cells, and are considered to play an important role in immune activation and generation of intestinal inflammation, the role of serotonin in function in the context of intestinal inflammation to In 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 experimental of colitis. TPH1−/− mice on C57BL/6 were produced by as by F. E. C. Y. M. E. N. F. L. M. Mallet J. G. of the the of peripheral serotonin in A. 2003; PubMed Scopus Google Scholar of the TPH1 has been by the mice are amounts of serotonin in the and show observed or from wild-type mice. of TPH1−/− mice and wild-type (TPH1+/+) were from and were and C57BL/6 were from were by the and the for to the in a of for J.E. Li N. Wang H. Collins M. Deng Y. El-Sharkawy R.T. Cote F. Mallet J. Khan W.I. Serotonin has a key role in pathogenesis of experimental colitis.Gastroenterology. 2009; 137: 1649-1660Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, J.E. Collins function to inflammatory bowel disease in a mouse of Clin Google Scholar were and of mice that have with the in a DSS-induced of ulcerative D.J. study of dextran sulfate sodium experimental Google Scholar is the of and were as to to to and and and presence and The from to after the of the the mice were and the the and on fluid and were The and and were using a system for D.J. study of dextran sulfate sodium experimental Google Scholar were and were with on a system that cell or and of inflammatory cell D.J. study of dextran sulfate sodium experimental Google Scholar after an between acid and infiltration in a of inflammatory bowel PubMed Scopus Google Scholar as a of and the using a of the by G. of of content with an Full Text PDF PubMed Scopus Google Scholar were in The and for The to a of and The of the by a is in of with the of to of to in were into small and for with and the cell treated with and cells were isolated by using mouse CD4+ T cells were isolated from the by using an mouse CD4+ T cell with as by using were using various The were and were from to various were on a using and using cells were from the and of naive mice as M.B. N. S. F. N. G. for large of highly dendritic cells from mouse 1999; PubMed Scopus Google Scholar and in of of amino sodium and of and after cells were with with cells from TPH1−/− mice were isolated as A of cells mouse were into TPH1−/− mice. DSS-induced colitis for DCs were with to of serotonin for cells from and TPH1−/− mice were isolated as DCs were and to lipopolysaccharide for The level of in the presence or of serotonin and DCs from mice treated with were and to for cocultured with CD4+ T cells isolated from naive mice a of G. A. of an in dendritic cells and its by A. 2010; PubMed Scopus Google Scholar in with of and of were and 7 for cytokine and levels and were using A in of were for and the levels and were using a and and levels were using a from by of of were and and to by addition of an of levels were using a are as using or of by the and considered We J.E. Li N. Wang H. Collins M. Deng Y. El-Sharkawy R.T. Cote F. Mallet J. Khan W.I. Serotonin has a key role in pathogenesis of experimental colitis.Gastroenterology. 2009; 137: 1649-1660Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar that in TPH1−/− mice that have reduced serotonin in the gut, colitis is significantly decreased after of and decreased significantly from to and to This in the severity of DSS-induced inflammation in TPH1−/− mice associated with down-regulation of and in and levels were significantly and DCs are critical in the production of in immune including associated with IBD. the by which serotonin is the of colitis, we the role of serotonin in function in relation to gut inflammation. DCs isolated from TPH1−/− mice with DSS-induced colitis significantly less compared with DCs isolated from TPH1+/+ mice stimulated with for a role of serotonin-mediated activation of DCs in the pathogenesis of colitis in in control we also observed a in the of in the of DCs of cell by revealed the of and on the isolated cells from both the TPH1+/+ and TPH1−/− mice cells isolated from TPH1+/+ mice and cells isolated from TPH1−/− mice and The role of serotonin in function by the of serotonin to naive DCs. A significantly of in the from naive TPH1−/− mice observed compared with TPH1+/+ mice addition of serotonin in of DCs from TPH1−/− mice significantly up-regulated production compared with DCs from TPH1−/− without the addition of serotonin of inhibitor in the significantly decreased the production of cytokines by DCs in to Serotonin significantly increased the levels of and effect by the addition of inhibitor We also investigated the effect of serotonin on dendritic cells from naive mice. were in the presence of to M.B. N. S. F. N. G. for large of highly dendritic cells from mouse 1999; PubMed Scopus Google Scholar Serotonin increased significantly the release of and in cell compared with A and We whether the of serotonin in the gut in TPH1−/− mice the of DCs to CD4+ T cells. CD4+ T cells isolated from naive mice and cocultured with DCs isolated from TPH1−/− mice significantly amounts of IL-17 and compared with CD4+ T cells cocultured with DCs isolated from TPH1+/+ mice stimulated with in control in the presence of we also observed a in the of IL-17 and in the of DCs We observed function of DCs isolated from TPH1−/− mice on and 7 of We investigated whether the transfer of serotonin-pulsed DCs from TPH1−/− mice the of an colitis in TPH1−/− mice. in the of colitis in mice serotonin-pulsed DCs, compared with DCs, in the in the and in the in The increased severity of colitis in mice serotonin-pulsed DCs also and The increased from in mice DCs to in mice transferred with serotonin-pulsed DCs. cytokine in the were also increased in mice serotonin-pulsed DCs. The in in mice serotonin-pulsed DCs compared with mice with DSS-induced colitis, and for and IL-17 were and of and IL-17 in were significantly increased mice were transferred with DCs The level significantly of adoptive transfer of DCs in TPH1−/− mice cytokine after induction of colitis. IL-17 and level in after of DSS-induced colitis. DCs cells with serotonin for increased of the different transferred to a TPH1−/− in compared with control compared with naive DCs. from of the adoptive transfer by the level of in and The in IL-12 significantly in in and in in mice serotonin-pulsed DCs compared with TPH1−/− DCs and Mucosal inflammation in from or colitis to is by alteration in EC cell numbers and serotonin content in the is that serotonin plays an important role in gut such as and fluid and is also emerging that the immune system EC cell and serotonin Y. Ghia J.E. Wang H. H. El-Sharkawy R.T. Collins M. Y. McLaughlin J.T. Khan W.I. Enterochromaffin cell and 5-hydroxytryptamine responses to the in and PubMed Scopus Google Scholar and serotonin plays an important role in the generation of intestinal inflammation and immune regulatory W.I. Ghia J.E. Gut hormones: emerging role in immune activation and inflammation.Clin Exp Immunol. 2010; 161: 19-27Crossref PubMed Scopus (146) Google Scholar, J.E. Li N. Wang H. Collins M. Deng Y. El-Sharkawy R.T. Cote F. Mallet J. Khan W.I. Serotonin has a key role in pathogenesis of experimental colitis.Gastroenterology. 2009; 137: 1649-1660Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, O. G. Li Chen Gershon M.D. of serotonin in intestinal of serotonin reuptake transporter sulfonic acid colitis in J Physiol Gastrointest Liver Physiol. 2009; PubMed Scopus Google Scholar the by which serotonin intestinal inflammation and immune cell function to DCs are key cells of an innate immune system and play a role in the generation of adaptive immune response. Because of the strategic location in the intestinal mucosa, DCs may with EC cells and perform a key role in the activation of the immune and the generation of gut inflammation. In for the to we of an role of serotonin in activation and generation of inflammation in the of experimental colitis. including mainly Crohn's disease and ulcerative colitis, is the most and inflammatory of the human bowel disease J PubMed Scopus Google Scholar, Collins The role of CD4+ in the of mice to of experimental 1999; PubMed Scopus Google Scholar Inflammation in the gut is characterized by mucosal recruitment of a of inflammatory cells, including T DCs, and cells. The release of inflammatory cytokines and activation of immune and inflammatory cells and the of the of cytokine and its as on the source and of inflammatory cytokine production is critical in in IBD. DCs are cells and are the of the immune response. DCs are for innate and adaptive immune response, also the and of adaptive immune responses in the context of the DCs have been in Crohn's disease pathogenesis and function of DCs and to have been to to the generation of intestinal A on dendritic cells and macrophages as key of mucosal Immunol. Full Text Full Text PDF PubMed Scopus (9) Google Scholar The of DCs in the pathogenesis of colitis has been by the that an increased number of DCs in the in the T-cell transfer of D. A. F. on dendritic cells in the colitis in T mice.J Immunol. PubMed Scopus Google Scholar and of DSS-induced colitis by of DCs after the of in receptor M. Chen The role of dendritic cells in the of dextran sulfate sodium Immunol. 2007; PubMed Scopus Google Scholar In DCs are of receptors is and DCs produce inflammatory cytokines, an important role of DCs in the pathogenesis of of intestinal dendritic cells in inflammatory bowel Full Text Full Text PDF PubMed Scopus Google Scholar is a intestinal inflammatory and the is characterized by the of innate and adoptive and proinflammatory F. A. of cytokines in inflammatory bowel J Gastroenterol. PubMed Scopus Google Scholar is by the IL-12 of cytokines produced by the activated T. of IL-12 and on the production of IL-17 by human T J Immunol. 2006; PubMed Scopus Google Scholar DSS-induced colitis is by the addition of to the and in a colitis characterized by mucosal inflammation with and innate and adaptive (TH1, TH17) immunological are to important in the pathogenesis of colitis in T. L. Chen M. Li cytokine from of and TNBS-induced 2009; PubMed Scopus Google Scholar, sulfate colitis in Full Text PDF PubMed Google Scholar Recent studies from demonstrated a key role of serotonin in the of DSS-induced colitis in TPH1−/− mice, which have reduced levels of serotonin in the J.E. Li N. Wang H. Collins M. Deng Y. El-Sharkawy R.T. Cote F. Mallet J. Khan W.I. Serotonin has a key role in pathogenesis of experimental colitis.Gastroenterology. 2009; 137: 1649-1660Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar This associated with the down-regulation of the production of proinflammatory cytokines and We also observed that of serotonin levels in TPH1−/− mice by the serotonin precursor increased the severity of DSS-induced colitis and the production of proinflammatory In we have of DSS-induced colitis in TPH1−/− mice compared with the TPH1+/+ mice. We also observed that reduced severity of colitis in TPH1−/− mice is with down-regulation of and levels in that there are in the in that may also to the immune activation and inflammatory after it important to that the reduced inflammation in TPH1−/− mice is to serotonin We investigated the levels of and as in the and observed of a in the levels of and between TPH1−/− and TPH1+/+ mice in DSS-induced colitis, that serotonin is the critical for the of inflammation in TPH1−/− mice after to on the proinflammatory role of serotonin studies that demonstrated that colitis by sulfonic acid or associated with is increased in severity with the of the of serotonin reuptake O. G. Li Chen Gershon M.D. of serotonin in intestinal of serotonin reuptake transporter sulfonic acid colitis in J Physiol Gastrointest Liver Physiol. 2009; PubMed Scopus Google Scholar, S. Y. O. Gershon M.D. of intestinal inflammation in mice by of the serotonin reuptake 2010; PubMed Scopus (69) Google Scholar The inflammation in DSS-induced colitis by reduced levels of production from DCs isolated from TPH1−/− mice compared with the DCs from TPH1+/+ mice. We also observed that DCs isolated from TPH1−/− mice produced significantly less in to compared with the TPH1+/+ mice. in vitro stimulation with serotonin restored production from DCs isolated from naive TPH1−/− mice. Serotonin also stimulated and production from which an important role of serotonin in receptors have been on M. Panther E. Stratz C. Muller T. Bayer H. Zissel G. T. S. F. M. Y. J. D. The serotoninergic receptors of human dendritic and to cytokine Immunol. 2004; PubMed Scopus Google Scholar and a study demonstrated that by to serotonin serotonin and serotonin 7 serotonin up-regulated production of proinflammatory cytokines and from T. T. M. S. Panther E. S. Y. F. D. J. M. 5-hydroxytryptamine cytokine and release and T-cell priming of dendritic cells in vitro and in 2009; PubMed Scopus Google Scholar has also been that by serotonin of inflammation, DCs may serotonin to naive T cells and T-cell and Wang M. C. A novel of immune signaling revealed by of the inflammatory mediator serotonin between dendritic cells and T 2006; PubMed Scopus Google Scholar of key proinflammatory and is to the and of inflammation in both human and in the mucosal immune system in ulcerative colitis and Crohn's Clin PubMed Scopus Google Scholar, C. K. of in immune and inflammatory responses in the 1998; PubMed Scopus Google Scholar Serotonin of gut inflammation by activation and production of proinflammatory cytokines from innate immune cells. In we observed that production of proinflammatory cytokines by DCs significantly by the addition of that serotonin plays an important role in activation of function the signaling and that the serotonin-mediated of function is critical in the pathogenesis of colitis in Because and immune responses have been characterized in DSS-induced T. L. Chen M. Li cytokine from of and TNBS-induced 2009; PubMed Scopus Google Scholar and DCs play a role in priming the immune to and cells, we whether reduced levels of serotonin in TPH1−/− mice have on T-cell priming and production of and demonstrated that DCs isolated from TPH1−/− mice a significantly reduced to naive CD4+ T cells in vitro to produce and IL-17 compared with the DCs isolated from TPH1+/+ mice. In addition, in studies on the adoptive transfer of serotonin-pulsed DCs, we observed a in and in TPH1−/− mice that serotonin-pulsed DCs with compared with the TPH1−/− mice that DCs without serotonin This associated with of and inflammatory cytokines and in of a role of serotonin in function in relation to generation of gut inflammation. studies show an important role of serotonin in the pathogenesis of inflammation in the gut by proinflammatory cytokine production from DCs activation of the and sequential T-cell on the of gut inflammation. In addition to of the pathogenesis of colitis, study provides novel information on serotonin in the context of immune cell Serotonin is to important in intestinal inflammation, studies have that serotonin of in A. F. Bader M. Serotonin in a mouse of Res. 68: PubMed Scopus Google Scholar and of by S. Li Gershon M.D. M. G. of serotonin synthesis is a for 2010; PubMed Scopus Google Scholar the from the present study are important in the of GI inflammation also in into the pathogenesis of disorders there is alteration in serotonin In a may have an implication in the role of gut in the pathogenesis of both GI and inflammation, which may ultimately lead to improved strategies in inflammatory disorders. We and Motomura for and

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