Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Abstract

IntroductionThe central and peripheral nervous systems can modulate immune function by releasing soluble factors such as hormones, neuropeptides, and neurotransmitters. 1,2 Serotonin (5-HT) is a classical neurotransmitter and vasoactive amine best known for its role in the regulation of variety of physiologic states and behaviors, including pain, appetite, mood, and sleep. 3 Despite these major roles for 5-HT in the central nervous system, the vast majority of 5-HT is produced in the periphery (Ͼ 90%), primarily by enterochromaffin cells in the gut. 4 Consistent with its abundance in the periphery, 5-HT is recognized as an important inflammatory mediator with significant immune-modulatory effects. 2,5 Mast cells and platelets both express the 5-HT specific transporter (SERT) which enables them to sequester 5-HT from the microenvironment. In turn, 5-HT is released in response to injury and/or inflammatory signals such as platelet activating factor, complement components (C3a and C5a), and IgE complexes. 5,6 Released 5-HT has been shown to regulate platelet aggregation 7 and to promote the accessory function of macrophages, and it is a potent eosinophil chemoattractant. 8,9 Consistent with these effects, 5-HT is implicated in the pathogenesis of inflammatory disorders, including asthma, inflammatory bowel syndrome, allergic diarrhea, and chronic eczema. 5,[10][11][12][13][14] Several studies have demonstrated that T and B lymphocytes are functionally responsive to 5-HT, implicating a role for this monoamine in the generation of adaptive immune responses. Inhibition of endogenous 5-HT synthesis can impair rodent T-cell proliferation. 2,15,16 Conversely, exogenous 5-HT is reported to suppress T-cell proliferation. 3 5-HT triggers the increased release of preformed IL-16 from CD8 ϩ T cells and can initiate delayedtype hypersensitivity reactions through the local recruitment and activation of CD4 ϩ T cells. [17][18][19] Thus, the precise role of 5-HT in modulating lymphocyte activation or function is currently ambiguous. Moreover, the identity of 5-HTRs expressed by T cells and the intracellular signaling pathways that transduce this signal remain unclear. 5-HTR signaling is complex with 7 recognized receptor subfamilies. 2 With the exception of the 5-HT 3 receptor, which is a ligand-gated ion channel, they belong to the family of 7 transmembrane G protein-coupled receptors. Both 5-HT 1 and 5-HT 2 receptor subfamilies have been implicated in signaling T cells. 3,[15][16][17]20,21 With rare exception, however, 20 most studies have only demonstrated the expression of 5-HTR gene transcripts or pharmacologic sensitivity to 5-HTR agonists or antagonists. 3 To elucidate the function of 5-HT signaling in T cells, we have made a comprehensive analysis of 5-HTR expression and signaling in primary mouse T cells. We show that naive T cells primarily express the 5-HT 7 receptor. Exogenous 5-HT leads to rapid phosphorylation of extracellular signal related kinase-1 and -2 (ERK1/2) and IB␣ in bulk naive T cells, early steps that ar...

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

“…Traditionally, it has been thought that the functions of immune cells such as T cells and DCs are regulated mainly by cytokines. However, a number of more recent studies have shown that immune system cells can also be regulated by neurotransmitters (6)(7)(8)(9)(10)(11). Consistent with this, both primary and secondary lymphoid organs are highly innervated by sympathetic ends that store dopamine (DA) (12,13).…”

Association between the use of serotonin receptor 2A–blocking antidepressants and joint disorders

“…The 5-HT 2A is linked to cell signaling through the JAK-2/STAT pathway (21), and there are studies suggesting that 5-HT 2A is present on activated T lymphocytes (4,5). One possible explanation, therefore, is that these joint ADRs could be of inflammatory origin.…”

“…Seven main groups of serotonin receptors with their corresponding subgroups have been identified (3). Serotonin receptor subtype 2A (5-HT 2A ) is located on neurons, but also on platelets, vascular smooth muscle (3), and probably also on immune cells (4,5).…”

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

“…These results further strengthen the notion that the 5-HT 7 receptor plays an important role in immune activation and colitis pathogenesis. It is important to note, however, that the 5-HT 7 receptor has also been shown to be expressed on T cells where they play an important role in early T cell activation events (71). Thus, treatment with SB-269970, for example, may also have an effect on T cells.…”