In addition, maturating dendritic cells undergo fundamental morphological changes by cytoskeleton reorganizations leading to the development of cellular extensions ( Hubo et al., 2013 Verdijk et al., 2004). For that, mature dendritic cells have to migrate to the secondary lymphoid organs, where they directly interact with naïve T cells to initiate immune responses ( Banchereau and Steinman, 1998 Harada et al., 2012 Müller et al., 2009 Randolph et al., 2005 Steinman, 1991). During this process, dendritic cells lose the ability to further uptake and process antigens, while gaining the capacity to activate T cells ( Banchereau et al., 2000 Langenkamp et al., 2000 Roses et al., 2008). lipopolysaccharide, LPS) induce the maturation of dendritic cells ( Ricart et al., 2011). Following tissue damage, increased levels of inflammatory chemokines, cytokines, and foreign antigens (e.g. In the steady state, immature dendritic cells continuously capture and take up self-antigens as well as injurious environmental proteins ( Steinman et al., 2003). They play a key role in the induction of immune responses by capturing and transferring antigens to the cells of the adaptive immune system ( Banchereau et al., 2000 Banchereau and Steinman, 1998 Figdor et al., 2004 Steinman and Witmer, 1978). Expression of 5-HT receptors has been identified on a broad range of immune cells, including T cells ( O'Connell et al., 2006), macrophages ( Mikulski et al., 2010) and dendritic cells ( Idzko et al., 2004).ĭendritic cells are important innate immune cells, which are known as the most effective antigen-presenting cells (APCs). Despite the major role of 5-HT in the CNS, ∼90% of 5-HT is produced in the gastro-intestinal tract ( Racké et al., 1996), where it is involved in the regulation of multiple physiological processes such as stimulation of cytokine and chemokine production ( Dürk et al., 2005 Idzko et al., 2004 Müller et al., 2009), cell proliferation ( Pakala and Benedict, 1998 Pakala et al., 1997), migration ( Kushnir-Sukhov et al., 2006 Müller et al., 2009 Tamura et al., 1997) and the regulation of the immune system ( Ahern, 2011). Serotonin receptors belong to the G-protein-coupled receptor family with exception of the 5-HT 3 receptor, which is an ion channel ( Barnes and Sharp, 1999). Serotonin operates by activating a family of specific 5-HT receptors, which comprise seven distinct classes based on their structural and functional characteristics. Serotonin (5-hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters in the central nervous system (CNS) regulating multiple physiological functions including the control of anger, aggression, body temperature, appetite, sleep, mood and pain ( Mössner and Lesch, 1998). Our results indicate that there is a crucial role for 5-HT 7R–Cdc42-mediated signaling in the regulation of dendritic cell morphology and motility, suggesting that 5-HT 7R could be a new target for treatment of a variety of inflammatory and immune disorders. Accordingly, migration of dendritic cells in murine colon explants was abolished after pharmacological receptor inhibition. Consistent with this, we observed that 5-HT 7R enhances chemotactic motility of dendritic cells in vitro by modulating their directionality and migration velocity. In addition, basal activity of 5-HT 7R was required for the proper expression of the chemokine receptor CCR7, which is a key factor that controls dendritic cell migration. Although dendritic cell maturation was independent of 5-HT 7R, receptor stimulation affected dendritic cell morphology through Cdc42-mediated signaling. Here, we demonstrate that expression of serotonin receptor 5-HT7 (5-HT 7R) as well as its downstream effector Cdc42 is upregulated in dendritic cells upon maturation. However, the functional role of serotonin receptors in regulation of dendritic cell functions is poorly understood. Inflammatory processes are often associated with an increased production of serotonin, which operates by activating specific receptors. Dendritic cells are potent antigen-presenting cells endowed with the unique ability to initiate adaptive immune responses upon inflammation.
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