Mast cells (MCs) are multifunctional immune cells derived from hematopoietic precursors implicated in the pathophysiological processes including allergic diseases, inflammation, autoimmunity, cancer, and neurodegenerative diseases (Kritas et al. 2013a, b, c, d; Starkl et al. 2013). MCs are found preferentially in intraepithelial locations, around blood vessels, bronchioles, and mucus-secreting glands, perform important beneficial roles in host defense, and are necessary for the development of allergic reactions, through cross-linking of their surface receptors for IgE (FcεRI), leading to degranulation, and release vasoactive, pro-inflammatory, and nociceptive mediators that include histamine, serotonin, pro-inflammatory, and anti-inflammatory cytokines and proteolytic enzymes (Table 1) (Petra et al. 2014). The relationship between the central nervous system (CNS) and the endocrine system has been known for many years and the neuroendocrine and immune systems are closely linked and are involved in a bidirectional communication. MCs are found in mammalian brains, especially in the hypothalamus. There is much evidence to suggest that MCs are capable of communication with nerves. MCs are located around the ganglion in adjacent leptomeningeal and connective tissues, as well as between the ganglion cells and nerve fibers, and are occasionally found in the posterior root of the ganglion (Panula et al. 1985). In addition, MCs interact with CNS where they secrete an array of potent mediators, including histamine, serotonin, tumor necrosis factor, interleukin (IL)-1, and other cytokines/chemokines (Theoharides et al. 2007). Therefore, the generation and release of neuropeptides activate endothelial cells, mast cells, and platelets to then increase extracellular levels of arachidonate metabolites, peptides, and ions (Theoharides et al. 2010).

Table 1 Mast cell mediators
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For many years, there has been great interest in the mechanisms of release of biogenic amines, and serotonin [5-hydroxytryptamine (5-HT)] is one of the most extensively studied neurotransmitters.

Serotonin (originally from serum plus tonic), a monoamine, is an important compound, which acts in both central and peripheral nervous systems and is one of the key mediators in signaling between the nervous system and the immune system (6). 5-HT is contained in cytoplasmic vesicles in enterochromaffin cells (Ahern 2011), as well as in platelets and MCs, with 5-HT being released when these cells are activated (Meuer et al. 1981; Papaliodis et al. 2008). The generation of 5-HT starts with hydroxylation of l-tryptophan at the fifth position on the indole ring to yield 5-HT, a reaction that requires molecular oxygen and the reducing cofactor 6-tetrahydrobiopterin; this reaction is catalyzed by tryptophan hydroxylase (TPH) an enzyme encoded by TPH1, which is expressed ubiquitously, while TPH2 genes are expressed predominantly in brain (Nordlind et al. 2008). The enzymes required to synthesize 5-HT from tryptophan are also present in the skin of certain animal species such as rodents. 5-HT is known to be produced and stored by murine MCs. However, a few studies have suggested the presence of serotonin in human MCs (Kushnir-Sukhov et al. 2008).

Increased doses of l-tryptophan proportionally increase 5-HT (or serotonin) formation. 5-HT is a bioactive mediator also implicated in MC adhesion, as well as chemotaxis, tumorigenesis, and tissue regeneration through induction of smooth muscle differentiation of bone marrow stromal cells (Hirota et al. 2014). Therefore, 5-HT mediates signaling by a wide range of neural and non-neural cells including mast cells. Moreover, the generation of 5-HT by mast cells is an important component for understanding mast cell function in the pathogenesis of inflammatory diseases and neurodegenerative disorders. The cellular sources of 5-HT in peripheral nerves are mostly platelets and mast cells (Sommer 2004). Immune cells express receptors for monoamine and intracellular serotonin transporters, and macrophages and murine mast cells have the ability to synthesize 5-HT. In addition, T cells are also able to produce 5-HT and to up-regulate its synthesis. Th1–Th2 cells, which are generated in human and animal models, are likely involved in resistance or susceptibility to brain diseases. T regulatory cells (Tregs) mediate protective immunity and inflammatory T-cell response to antigens. Tregs can easily differentiate into inflammation-associated Th17 which along with IL-23 are strongly associated with psoriasis a psycho-neuroimmunological and autoimmune-related chronic inflammatory skin disease (Mashayekhi et al. 2014). Moreover, Tregs and CD4+CD25(high)Foxp3+ are strong immunomodulators and are likely to play a major role in cancer development and are typically considered inhibitors of autoimmune responses including CNS disorders. 5-HT participates in T-cell activation via phosphorylation of extracellular signal-related kinase-1 and -2 (ERK1/2) (Bovenschen et al. 2011). Naive T cells, regulated by 5-HT, express the 5-HT receptor (Stefulj et al. 2001), however, the exact role of 5-HT in modulating immune function, particularly T-cell function, remains to be clarified.

In the brain, 5-HT neurons play a part in sleep–wakefulness cycles, mood, emotional and food behaviors, and thermoregulation, and in pathophysiological conditions, such as depression and insomnia (Jha et al. 2005). The strategic position of 5-HT suggests its involvement in the transduction of organ stimuli and reflex responses affecting motor and secretory function. Changes in serotonin concentration may occur in sensory innervation or pathways within the CNS leading to pain and hypersensitivity (Suter et al. 2007), an effect also mediated by MCs. In addition, when injected subcutaneously, 5-HT produces edema and increases capillary permeability, an important effect on peripheral and pulmonary vascular smooth muscle (Maleki-Dizaji et al. 2010). Since MCs tend to be in juxtaposition to blood vessels, 5-HT is expected to be secreted to act on these vessels. Therefore, 5-HT and its receptors are involved in hypersensitivity and inflammation (Enerbäck 1965) (Table 2). The release of serotonin by intracellular granules of MCs in humans is possibly regulated by the influx of Ca2+, an effect also highlighted in mast cell lines and freshly isolated peritoneal mast cells in experimental rodent models (Gordon and Galli 1991).

Table 2 5-HT receptor expression in several cell types
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5-HT is present in murine mucosal MCs in the lamina propria; some authors have reported that human mast cells may also contain serotonin, especially in subjects with mastocytosis. In such patients, abnormal blood levels of 5-HT have been reported (Kushnir-Sukhov et al 2007; Metcalfe 1984). 5-HT is considered to be an inflammatory mediator in the periphery, being released from platelets and mast cells after tissue injury, to exert direct actions on C-fibers (Sommer 2004).

Human MC cultures in vitro contained less than 1 ng/mL of 5-HT, while mouse mast cells contained about tenfold more (22). In addition, some studies revealed the presence of mRNA and protein for tryptophan hydroxylase in human mast cells and concluded that human mast cells contain and release 5-HT (Kushnir-Sukhov et al. 2007; Metcalfe 1984).

Neurotransmitter 5-HT modulates antigen presenting cells, lymphocytes, and macrophages and is implicated in cytokine/chemokine generation and inflammation (Aune et al. 1993). Cytokines/chemokines are present in the hypothalamic–pituitary–adrenal axis, and inflammatory cytokines/chemokines produced within the brain may affect the course of neurodegenerative diseases (Cao et al. 2005). Pituitary gland generates several cytokines including IL-2, IL-1, TNF, and IL-6 (Kielian et al. 2004).

IL-6, a 26,000 molecular weight B-cell differentiation cytokine, is synthesized and released within neuroendocrine structures such as glia and astrocytes of the CNS, and stimulates prolactin, GH, and luteinizing hormone (LH) release from anterior pituitary cells in vitro (Jara et al. 2001). Certain pro-inflammatory cytokines such as IL-1, TNF, IL-6, and IL-33 regulate intracellular communication and are often elevated in a number of psychiatric conditions (Gemma et al. 2000). They are also involved in autoimmune diseases and cancer (Kritas et al. 2013a, b, c, d). In addition IL-1β regulates IL-6 release and induces several chemokines from neuroendocrine cells, demonstrating that products of the immune system, such as cytokines and chemokines may affect neuroendocrine activation and cell proliferation (Spangelo et al. 2000). Cytokines can mediate the release of 5-HT and other pro-inflammatory compounds from CNS mast cells, a process that contributes to inflammation and probably mortality. Therefore, in neuropathological diseases, cytokines have access to the CNS and are expressed in the brain, altering the metabolism and perhaps releasing 5-HT (Spangelo et al. 2000). The two potent pro-inflammatory cytokines, IL-1-β and TNF, are able to activate p38 MAPK in peripheral systems (28) and might increase 5-HT activity through p38 MAPK activation (Baud et al. 1999).

Several neuropeptides induce MC 5-HT release and may mediate neuroendocrine-linked mast cell activation (Hu and Tang 2009). It is proposed that MCs are capable of playing a more general transduction role, instead of acting as an immune cell, and may be capable of responding to a variety of stimuli (Sharkey and Mawe 2002).

5-HT and its receptor 5-HT1AR are expressed in human mastocytosis, and an agonist of the 5-HT1AR could be of value in the treatment of these patients (Ritter et al. 2012). 5-HT has seven specific cell surface membrane bound receptors (R) which are coupled to G-proteins (Sodhi et al. 2001) (Table 3).

Table 3 Effects of 5-HT receptor agonists and antagonists
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5-HT syndrome is caused by hyperstimulation of 5-HT1A receptors in central gray nuclei and the medulla, and perhaps hyperstimulation of 5-HT2 receptors as well (Klimek et al. 1994). Besides its general effects, 5-HT also has an impact on cell proliferation, migration, and apoptosis (Kritas et al. 2014a, b, c, d). 5-HT1A receptor-positive MCs, and 5-HT2A receptor, and 5-HT reuptake transporter-positive T lymphocytes may be targets for drug therapy (Noro et al., 2010). It has been reported that in the apical epidermis of atopic eczematous of human skin melanocytes, MCs express 5-HT1A receptors (Ando et al. 2013; Kim 2012). In addition, we previously reported that chemokines RANTES/CCL5, MCP-1/CCL2, and related molecules constitute the C–C class of chemokine supergene family, playing a role in regulating Th-cell cytokine production and MC trafficking, and are involved in histamine and 5-HT generation and cell function in mast cells (Kritas et al. 2013a, b, c, d). Using immortal tumor-derived cell lines such as rat basophilic leukemia 2H3 (RBL) cells, it has been shown that CXCL10 (CXCR3 ligand) and CCL5 (CCR5 ligand) chemoattract mast cells in the site of inflammation and generate small amounts of serotonin and other granule mediators, increasing vascular dilation (Gruba et al. 2014). Recently, it has been shown that mast cell degranulation also involves CXCL10 and CCL5 which are two important related inflammatory chemokines (Sepiashvili et al. 2013). Therefore, CXCL10 and CCL5 chemokines play an important role on MC activation through a different pathway than IgE-mediated allergen stimulation (Kritas et al. 2014a, b). 5-HT and other mediators alter vascular dilation (46) and CXCL10 and CCL5 function, allowing mast cells to migrate to sites of inflammation, including sites in the CNS (Juremalm et al. 2005; Kritas et al. 2014c).

Smooth muscle constitutively expresses transforming growth factor (TGF)-β1, and its release is mediated by 5-HT. This effect demonstrates that 5-HT promotes smooth muscle differentiation and tissue remodeling, contributing to the pathogenesis of several neurological diseases (Hirota et al. 2014).

5-HT-containing mast cells are also involved in intestinal inflammation and the mobilization of 5-HT attributable to specific pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF (Hajj Hussein et al. 2014; Komiyama et al. 2011). Therefore, neuroimmune interactions and tissue inflammation, which can also be mediated by stress (Papathanasiou et al. 2013), are regulated by a number of factors including MC-derived 5-HT generated under the influence of IL-3 [termed multi-colony-stimulating-factor (multi-CSF) or mast cell growth factor] produced by T-cells, causing severe hypersensitive reactions and playing a pivotal role in exacerbating the inflammatory response in vivo (Conti et al. 1995; Prevete et al. 2013).

5-HT has been reported to be involved in blood–brain barrier permeability. Where blood barrier opening is seen, there is evidence for activation of 5-HT2 receptors and a Ca2+-dependent permeability increase and augmentation of inflammatory mediator effects. Therefore, there is a clear intercommunication between mast cells and CNS, and this crosstalk suggests a functional connection. Inhibition of MC mediators, including 5-HT, may hold promise for therapeutic intervention of neuroinflammatory diseases (Abbott 2000; Kritas et al. 2013a, b, c, d).

Neurotransmitters (such as substance P) in contact with mast cells cause MC degranulation, an effect increased in acute stress in mice. Mast cells increase also in lesional psoriatic skin, and there appears to be an association among sensory nerves, mast cell numbers, and stress. It is interesting that psoriasis is worsened by acute stress, although it is not known whether 5-HT is involved in this disease (Theoharides et al. 2010).

Stimulated mast cells produce also IL-33 or IL-1F11 which is one of the newest inflammatory members of the IL-1 family, synthesized as a 31-kDa peptide precursor cleaved by caspase-1 to generate mature cytokine IL-33 (Dinarello 2005). This interleukin acts by binding its receptor T1/ST2 (Toll-IL-1 receptor), an orphan member of the IL-1 receptor family, activating NF-κB pathway, and MAP kinases. This process induces biological effects in mast cells: increasing in mice the production of IL-4, IL-5, and IL-13 which suppress the differentiation of inflammatory lymphocyte Th1 while increasing Th2 in adaptive immunity (Castellani et al. 2009). In mast cells, IL-33 stimulates production of arachidonic acid products such as PGD2 and inflammatory cytokines including TNF, MCP-1, and time-dependent stimulated IL-6 secretion, while it fails to release IL-2, IL-4, IL-5, or alter tryptase activity (Dinarello 2005). Substance P (SP), an undecapeptide belonging to a group of proteins termed tachykinins, is the key transmitter of pain to the brain and an activator of mast cells in several inflammatory diseases, including stress and neurological dysfunctions (Boyd and Leeman 1987). Whenever fibers come into contact with SP, they react by swelling—an effect that produces headache and sinus symptoms. In MCs, SP strongly induces the release of VEGF, chemoattractants, and promotes secretion of a number of intracellular molecules such as 5-HT and histamine (Shaik-Dasthagirisaheb et al. 2013a, b). IL-33 may play an important role in asthma, allergic-type diseases, and neurological disorders, without direct activation of 5-HT (61). IL-33 is abundantly expressed by endothelial veinules, and when injected into mouse, it causes several pathological effects in the mucosal tissues and brain such as eosinophilia and an increase of mast cell number, without mast cell degranulation (Theoharides et al. 2010). We recently found that IL-33 is a strong activator of human mast cell lines (LAD II cells) able to induce MCP-1, IL-8, TNF, and VGEF release at the transcriptional and translational level, suggesting a possible role of this new cytokine in inflammatory responses and in neurological disorders (Theoharides et al. 2010). However, it is still unknown whether IL-33 is implicated in the generation and release of 5-HT. Collectively, these observations suggest that IL-33 is a central regulator of mast cell responses. These studies may therefore implicate MCs and 5-HT as novel targets for the treatment and control of allergies, as well as autoimmune and neurodegenerative diseases. Nevertheless, the exact biological role of IL-33 and its molecular mechanisms regulating MC remain to be defined.

Natural compounds such as quercetin and capsaicin have a negative effect(s) on intracellular regulator signal events initiated by FcεRI receptor cross-linking and other activating receptors with an inhibitory effect on mast cells (Frydas et al. 2013; Shaik-Dasthagirisaheb et al. 2013a, b). It would be interesting to see the effect(s) of these natural compounds on the generation of 5-HT and other mediators derived from degranulated and non- degranulated activated MCs (Karamitopoulou et al. 2014).

The purpose of this paper was to review and possibly clarify the relationship between MCs and 5-HT in inflammation. The present report indicates that modulation of 5-HT may have a role in MC function and differentiation. However, further studies on the effects of MC-secreted cytokines/chemokines and 5-HT are needed to better understand the complex role that mast cell activation plays in inflammatory and neurodegenerative diseases.