Role of 5-HT7 receptors in the immune system in health and disease

Abstract

In mammalians, serotonin (5-HT) has critical roles in the central nervous system (CNS), including mood stability, pain tolerance, or sleep patterns. However, the vast majority of serotonin is produced by intestinal enterochromaffin cells of the gastrointestinal tract and circulating blood platelets, also acting outside of the CNS. Serotonin effects are mediated through its interaction with 5-HT receptors (5-HTRs), a superfamily with a repertoire of at least fourteen well-characterized members. 5-HT7 receptors are the last 5-HTR member to be identified, with well-defined functions in the nervous, gastrointestinal, and vascular systems. The effects of serotonin on the immune response are less well understood. Mast cells are known to produce serotonin, while T cells, dendritic cells, monocytes, macrophages and microglia express 5-HT7 receptor. Here, we review the known roles of 5-HT7 receptors in the immune system, as well as their potential therapeutic implication in inflammatory and immune-mediated disorders.

Introduction

Serotonin (5-hydroxytryptamine [5-HT]), a monoamine neurotransmitter discovered over seven decades ago as a vasoconstricting agent (Rapport et al. 1948), has critical -and well defined- roles in the central nervous system (CNS), including regulation of mood stability, pain tolerance, or sleep patterns to name a few. Serotonin receptors are expressed throughout the immune system (Herr et al. 2017; Ahern 2011). 5-HT₇ receptor is a member of the family of serotonin receptors, originally cloned in 1993 (Bard et al. 1993; Lovenberg et al. 1993; Ruat et al. 1993) a little more than a decade after the first receptor, 5-HT₁ receptor, was (Peroutka and Snyder 1981). Like other serotonin receptors, 5-HT₇ receptors are members of the G protein-coupled receptor superfamily. Their activation leads to the initiation of two well-characterized signaling pathways: the canonical signaling occurs through Gαs, while a non-canonical pathway signals through Gα12 (Guseva et al. 2014b). Different 5-HT₇ receptor isoforms have been described (5-HT_7a, 5-HT_7b, 5-HT_7d, all expressed in humans and rats, as well as 5-HT_7c, expressed only in rats) differing only on the carboxy terminus length, nonetheless, no relevant functional differences have been observed between them (Liu et al. 2001).

Distribution of 5-HT7 receptors

5-HT₇ receptors are expressed mainly in two compartments: the CNS (Hedlund and Sutcliffe 2004) and the gastrointestinal (GI) tract (Yaakob et al. 2015), although they are also expressed in other tissues including immune cells (see below). In the CNS, the receptor is broadly expressed in the spinal cord, suprachiasmatic nucleus of the hypothalamus, antedorsal thalamus, globus pallidus, prefrontal cortex, trigeminal nucleus caudalis, raphe nuclei area, amygdala and hippocampus, particularly in pyramidal cells of cornu ammonis (CA)1 and CA3, where they are expressed in both, neurons and glial cells, including microglia, the CNS-specific phagocytic cell (Chapin and Andrade 2001; Dogrul and Seyrek 2006; Gill et al. 2002; Horisawa et al. 2013; Thomas and Hagan 2004; Tokarski et al. 2003; Russo et al. 2005; Hedlund and Sutcliffe 2004; Lovenberg et al. 1993).

5-HT₇ receptors are found on smooth muscle cells in several arteries, including the aorta, cerebral, coronary, and pulmonary arteries, where their primary known role is to induce vasodilation (Jasper et al. 1997; Nilsson et al. 1999; Jähnichen et al. 2005; Chang Chien et al. 2015; Terrón and Falcón-Neri 1999). In the GI tract, 5-HT₇ receptors are expressed not only in gut-associated neurons, but also in enterocyte-like and immune cells in lymphatic tissues scattered all along the gut (Iceta et al. 2009; Kim et al. 2013; Guseva et al. 2014b), including monocytes, lymphocytes and dendritic cells (DCs) (León-Ponte et al. 2007; Wu et al. 2019), where it may play a crucial role in inflammation signaling (Urbina et al. 2014; Soga et al. 2007; Holst et al. 2015). Also, 5-HT₇ receptors are found in neutrophils, but the net effect of 5-HT₇ receptor signaling and modulation on neutrophil function is yet to be defined (Rapalli et al. 2016). 5-HT₇ receptors have also been identified in hepatic stellate cells and hepatocytes (Ruddell et al. 2006; Svejda et al. 2013).

Of direct relevance to the present review, 5-HT₇ receptors are also present in immune tissues, including the spleen and thymus; peripheral blood (Stefulj et al. 2000); DCs and other bone marrow-derived mononuclear cells (Shen et al. 1993; Vanhoenacker et al. 2000; Idzko et al. 2004).

Methods

We performed a comprehensive search of English language literature to identify all original research, and review articles regarding 5-HT₇ receptors, signaling pathways and the effects on the immune system; PubMed database since 1993 was used. We used the following Medical Subject Headings (MeSH) and main keywords for searches: 5-HT₇, LP-211, LP-44, LP-21, AS-19, SB 269970, 5-HT₇ physiology, 5-HT₇ receptor mechanism of action, 5-HT₇ receptor signaling pathway, 5-HT₇ receptor effect, 5-HT₇ receptor distribution, inflammation, dendritic cell, microglia, macrophages, and lymphocytes. We also reviewed the reference lists of the articles identified during the search. The authors independently reviewed the selected articles.

Signaling pathways

There are at least two separate signaling pathways downstream of 5-HT₇ receptors (Fig. 1). The activation of the canonical signaling pathway leads to the phosphorylation of different adenylyl cyclases (AC), specially AC1 and AC8 (Baker et al. 1998). The increased activity of AC results in an increased production of cyclic adenosine monophosphate (cAMP), activation of protein kinase type A (PKA) and subsequently the phosphorylation of different target proteins like extracellular signal-regulated kinase (ERK) and Protein kinase B (also known as Akt) (Errico et al. 2001; Johnson-Farley et al. 2005). Signaling through the non-canonical pathway leads to activation of Gα12, whose downstream activity is mainly exerted by the Rho family of small guanosine triphosphate (GTP)-ases (Rho, Rac, cell division control protein 42 [Cdc-42]) (Guseva et al. 2014b).

Interestingly, 5-HT₇ receptors may interact with other members of the 5-HT family of receptors. For instance, there is a well-characterized interaction between 5HT₇ and 5-HT_1A receptors. 5-HT₇ receptors can form heterodimers with 5-HT_1A receptors, resulting in a reduction in the activity of 5-HT₇ receptor (Renner et al. 2005). Moreover, 5-HT_1A also inhibits the same signaling cascade as 5-HT₇ receptor-mediated Gs (Zhou et al. 2019). Although to our knowledge no study has demonstrated a biological effect of this crosstalk in the immune system, this interaction could potentially explain the neutral effect of serotonin or SSRI administration.

In neuroblastoma cells, activation of 5-HT7 receptors induces the formation of filopodia via a Cdc-42-mediated pathway (Kvachnina 2005); in cultured hippocampal neurons, promotes the formation of dendritic spines and accelerates synaptogenesis; moreover, in cultured striatal and cortical neurons, activation of Gα12 leads to pronounced neurite growth via the activation of cyclin-dependent kinase 5 (Cdk5) and ERK (Speranza et al. 2013). All that suggests that 5-HT₇ receptor signaling is critical for synaptogenesis and cell-cell communication which may also occur between non-neuronal cells, including immune ones as will be discussed below.

Effects of 5-HT7 receptor signaling in immune cells

Dendritic cells

5-HT₇ receptors are highly expressed in mature, but not immature DCs (Idzko et al. 2004; Holst et al. 2015). 5-HT₇ receptor activation induces DCs to release interleukin (IL)-1β and IL-8, while reducing the secretion of IL-12 and tumor necrosis factor (TNF)-α (Idzko et al. 2004). As observed in neurons, 5-HT₇ receptor signaling in mature DCs also induces process branching and elongation via Cdc-42. While DCs do not show chemotactic response to 5-HT₇ receptors, the non-selective high-affinity agonist 5-carboxamidotryptamine enhances velocity and distance of the chemotactic response to chemokine ligand (CCL)19 (Holst et al. 2015). The above mentioned data is summarized in Table 1.

Monocytes and macrophages

Experimental evidence has shown an in vitro effect of 5-HT₇ receptors on these cells, but the net effect is still incompletely understood. Monocytes treated with serotonin, or methiothepin maleate (a non-specific 5-HT_1/6/7 receptor agonist), exhibit an inflammatory and anti-apoptotic polarization, including upregulation of TNF-α and IL-6, as well as upregulation of the transcription factors B-cell lymphoma 2 (Bcl-2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB); and inhibition of caspase-3. Moreover, treating monocytes with serotonin resulted in increased expression of the costimulatory molecules cluster of differentiation (CD) 40, CD80, and CD86, but not of MHC class II molecules (Soga et al. 2007). In contrast, the selective 5-HT₇ receptor antagonist SB 269970 reverts the anti-inflammatory effect of serotonin on dextran sodium sulfate (DSS)-stimulated M2 macrophages, increasing the production of TNF-α and IL-12, while also interfering with polarization (de las Casas-Engel et al. 2013).

In human and murine macrophages, it has been recently shown that serotonin (as well as AS19, a selective 5-HT₇ receptor agonist) decrease inflammatory priming, in part by reducing the production of IL-12, TNF-α, and type 1 interferons, as well as enhancing the production of transforming growth factor β 1 (TGF-β1). Moreover, 5-HT₇ receptor signaling promotes pro-fibrotic gene signature in a 5-HT₇ and PKA-dependent manner (Domínguez-Soto et al. 2017).

A role for 5-HT₇ receptors has been experimentally observed in murine models of skin fibrosis and DSS-induced colitis. In the former, macrophage infiltration and collagen deposition are blunted by genetically or chemically interfering with 5-HT₇ receptor signaling (Domínguez-Soto et al. 2017). Oral administration of DSS results in a well-characterized model of gastrointestinal inflammation. Interestingly, DSS also results in increased expression of 5-HT₇ receptors in a subset of anti-inflammatory myeloid (CD11b⁺CD68⁺) cells, suggesting that myeloid expression of 5-HT₇ receptors may also –under specific insults- attenuate the inflammatory response (Guseva et al. 2014a).

Microglia

These, CNS-specific phagocytic mononuclear cells (Wolf et al. 2017), are produced in the yolk sac and migrate during early CNS development, before the blood brain barrier is formed. In adult life, microglia are involved in a number of homeostatic functions, including neurogenesis, synaptogenesis and synapsis remodeling, as well as neuronal apoptosis and removal (Li and Barres 2018). Microglia also actively survey the CNS for preserved molecular patterns suggestive of infection (pathogen-associated molecular patterns [PAMPs]) and tissue injury (damage-associated molecular patterns [DAMPs]) (Sankowski et al. 2015; Salter and Stevens 2017). Adult microglia express several serotonin receptors, including 5-HT_2a, 5-HT_2b, 5-HT_5a, and 5-HT₇ receptors (Krabbe et al. 2012). Microglia express at least two splice variants of the 5-HT₇ receptor: 5-HT_7(a/b). In these cells, the administration of serotonin, as well as 5-carboxamidotryptamine (5-CT) induces an inflammatory priming and IL-6 production, indicating that these receptors may play a role in CNS inflammation and repair (Mahé et al. 2005).

T cells

Lymphocytes express functional serotonin receptors (Cedeño et al. 2005; Müller et al. 2009). However, information on the role of 5-HT₇ receptors in lymphoid cells is scant. However, preliminary evidence indicates that lymphocytes obtained from rats exposed to either concanavalin A, reserpine, or physical restraint have an increase in number of 5-HT₇ receptor-positive lymphocytes, as well as increased expression of 5-HT₇ mRNA (Urbina et al. 2014). Naïve splenic T cells express 5-HT₇ receptors; their ex vivo exposure to serotonin leads to a rapid 5-HT₇ receptor-dependent phosphorylation of ERK 1/2, increased proliferation rate, and increased expression of CD25; that response is abrogated by the 5-HT₇ receptor antagonist SB 269970 (León-Ponte et al. 2007). Together, this suggests that 5-HT₇ receptors play a role in T cell responses to inflammatory stimuli.

Neutrophils

While neutrophil migration can be regulated through the effect of serotonin in other receptors, current evidence suggest that 5-HT₇ receptor has no role on neutrophil recruitment (Rapalli et al. 2016).

Hepatocyte response to injury

The above mentioned data is summarized in Table 1. Serotonin has been observed to play a role in liver remodeling in response to inflammatory injury, but the mechanism is incompletely understood. Current evidence suggests that hepatocyte proliferation may be regulated by 5-HT receptors at a number of levels. An in vitro study on rat hepatocytes showed that 5-HT₇ receptor activation by serotonin dose-dependently increases cAMP and PKA signaling, whereas the pharmacological blockade by SB 269970 (a highly specific antagonist) reverted this effect, an observation with potential implications for extra-hepatic tumor seeding to the liver (Svejda et al. 2013).

Organ and disease specific effects of 5-HT7

Sepsis

In lipopolysaccharide (LPS)-induced sepsis, lung expression of 5-HT₇ receptors increases in parallel to the increased expression of TNF-α, IL-1β, and NF-κB. Moreover, in that model, activating 5-HT₇ receptors with LP44 attenuates LPS-induced cell injury, reducing the levels of inducible nitric oxide synthase (iNOS) and TNF-α in a dose-dependent manner (Ayaz et al. 2017).

Cecal ligation and puncture (CLP) is a well validated model of severe poli-microbial sepsis that results in acute and chronic inflammation (Valdés-Ferrer 2014; Buras et al. 2005; Valdés-Ferrer et al. 2013). Administration of a selective 5-HT₇ receptor agonist (AS19) in a rat model of CLP-induced sepsis results in increased survival, decreased tissue injury, a reduction in circulating inflammatory cytokines (IL-1β, IL-6 and TNF-α), an increase in antioxidant mediators (superoxide dismutase and glutathione), and a reduction in lung NF-κB (Cadirci et al. 2013). The above mentioned data is summarized in Table 1.

Inflammatory bowel disease

5-HT₇ receptors are expressed in enteric neurons and CD11c⁺ DCs in the colon; as mentioned above, 5-HT₇ receptor expression is significantly increased after the induction of colitis by DSS (Domínguez-Soto et al. 2017). In that model, the blockade or genetic ablation of 5-HT₇ receptors results in increased severity of acute and chronic colitis; in contrast, 5-HT₇ receptor agonists result in an anti-inflammatory effect (Guseva et al. 2014a; Kim et al. 2013). However, pharmacological blockade of 5-HT₇ receptors has no effect in 2, 4, 6 trinitrobence sulfonic acid-induced colitis (Rapalli et al. 2016), suggesting that the inflammatory effect of 5-HT₇ receptors is model-specific. More studies of the downstream-signaling mediators are needed to further understand the therapeutic potential of 5-HT₇ receptors in experimental inflammatory bowel disease.

Lung inflammation

Bleomycin induces experimental pulmonary fibrosis (Adamson and Bowden 1974). During the acute inflammatory phase, 5-HT₇ receptor antagonists decrease lung fluid content, inflammatory cytokines (TNF-α, IL-6) and oxidative stress burden. In the chronic fibrogenic phase, 5-HT₇ receptor antagonism reduces collagen deposition, and mRNA expression of TGF-β1 and procollagen type Ӏ (Tawfik and Makary 2017). In contrast, in CLP-induced sepsis, 5-HT₇ receptor agonists reduce pro-inflammatory mediators and increase survival (Cadirci et al. 2013). Altogether, the current evidence is ambivalent regarding the usefulness of pharmacologically interfering with 5-HT₇ receptor signaling in experimental lung injury.

Liver disease

To our knowledge only one study has focused on the effect of 5-HT₇ receptor signaling during chronic liver injury induced by carbon tetrachloride. There, 5-HT₇ receptor agonists reduced alanine transaminase (ALT) and aspartate transaminase (AST) levels; increased the level of superoxide dismutase; and decreased the levels of TNF-α, IL-6 and TGF-β1. By the same token, 5-HT₇ receptor antagonism increases cytokines levels. In their histopathological analysis, the carbon tetrachloride group showed severe vacuolar degeneration, necrosis, irregular walls of the vena centralis and lytic areas. In contrast, the administration of the 5-HT₇ receptor agonist LP-44 partially rescued animals from liver damage. This suggests that 5-HT₇ receptors may be a potential therapeutic target for chronic liver inflammation (Polat et al. 2017).

Alzheimer disease (AD)

Immune activation in response to inflammatory insults is a key mediator of neurodegeneration in AD, depression, as well as other CNS disorders (Baganz and Blakely 2013; Strasser et al. 2016). Microglia engulfs and degrades β-amyloid, leading to an excessive release of inflammatory cytokines that further propagate inflammatory damage (Holmes and Butchart 2011). Also, β-amyloid binds to receptors for advances glycation end products (RAGE), resulting in further microglia activation (Querfurth and Laferla 2018). In an AD animal model, the intracerebroventricular (ICV) administration of LP-211 (a 5-HT₇ receptor specific agonist) inhibited the neurotoxic effect of β-amyloid in hippocampus (Quintero-Villegas et al. 2018). In a rat model of stroptozotocin-induced AD, ICV administration of the 5-HT₇ receptor-selective agonist AS19 rescued neuronal apoptosis and synaptic dysfunction (Hashemi-Firouzi et al. 2017). Altogether, available preliminary evidence derived from animal models indicates that pharmacological manipulation of the 5-HT₇ receptor may have a niche in the treatment of AD.

Soft-tissue inflammation

The above mentioned data is summarized in Table 1. In a carrageenan-induced paw inflammation model, 5-HT₇ receptor agonists reduced cyclooxygenase mRNA expression, decreased oxidative stress and serum cytokine levels (Albayrak et al. 2013).

Conclusions

5-HT₇ receptors are widely expressed in a vast repertoire of immune and non-immune cells. The receptor has diverse -and even discrepant- roles in the immune response, probably a reflection of at least two clearly defined signaling pathways: in dendritic cells it induces the secretion of IL-1 and IL-6; in monocytes, for instance, it may either be pro- or anti-inflammatory; while in lymphocytes it increases the proliferation rate, suggesting a proinflammatory pattern.

Regarding an organ-specific effect, in CNS, soft tissue, and liver inflammatory injury, the net effect of 5-HT₇ receptors is anti-inflammatory (reducing cell death, inflammatory cytokine release, and oxidative stress). In models of severe sepsis, 5-HT₇ receptor agonists have resulted in a net anti-inflammatory effect. In contrast, bleomycin-induced lung injury is the only experimental model where 5-HT₇ receptors seems to be pro-inflammatory. In experimental murine inflammatory bowel disease, the effect of 5-HT₇ receptors has shown contradictory results.

While our understanding of the connection between 5-HT₇ receptors and inflammation is still limited, significant advances have emerged in the past two decades. Nonetheless, current evidence suggests that pharmacological interventions targeting 5-HT₇ receptors may be potentially useful for treating inflammatory conditions.

Acknowledgements

AcknowledgementsThe figures on this manuscript were done using biorender.com software.

Competing interests

Competing interestsThe authors declare that they have no competing interests.

References

1. Adamson IY, Bowden DH. The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol. 1974 PubMed
2. Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol. 2011 doi:10.1016/j.coph.2011.02.004 PubMed
3. Albayrak A, Halici Z, Cadirci E, Polat B, Karakus E, Bayir Y et al. Inflammation and peripheral 5-HT7 receptors: the role of 5-HT7 receptors in carrageenan induced inflammation in rats. Eur J Pharmacol. 2013 doi:10.1016/j.ejphar.2013.05.010 PubMed
4. Ayaz G, Halici Z, Albayrak A, Karakus E, Cadirci E. Evaluation of 5-HT7 receptor trafficking on in Vivo and in vitro model of lipopolysaccharide (LPS)-induced inflammatory cell injury in rats and LPS-treated A549 cells. Biochem Genet. 2017 doi:10.1007/s10528-016-9769-2 PubMed
5. Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci. 2013 doi:10.1021/cn300186b PubMed
6. Baker LP, Nielsen MD, Impey S, Metcalf MA, Poser SW, Chan G et al. Stimulation of type 1 and type 8 Ca 2+ /Calmodulin-sensitive adenylyl Cyclases by the G s -coupled 5-Hydroxytryptamine subtype 5-HT 7A receptor. J Biol Chem. 1998 doi:10.1074/jbc.273.28.17469 PubMed
7. Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL. Cloning of a novel human serotonin receptor (5-HT7) positively linked to Adenylate Cyclase. J Biochem Chem. 1993 PubMed
8. Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov. 2005 doi:10.1038/nrd1854 PubMed
9. Cadirci E, Halici Z, Bayir Y, Albayrak A, Karakus E, Polat B et al. Peripheral 5-HT7 receptors as a new target for prevention of lung injury and mortality in septic rats. Immunobiology. 2013 doi:10.1016/j.imbio.2013.04.012 PubMed
10. Cedeño N, Urbina M, Obregón F, Lima L. Characterization of serotonin transporter in blood lymphocytes of rats. Modulation by in vivo administration of mitogens. J Neuroimmunol. 2005 doi:10.1016/j.jneuroim.2004.09.010 PubMed
11. Chang Chien CC, Hsin LW, Su MJ. Activation of serotonin 5-HT7 receptor induces coronary flow increase in isolated rat heart. Eur J Pharmacol. 2015 doi:10.1016/j.ejphar.2014.08.027 PubMed
12. Chapin EM, Andrade R. A 5-HT(7) receptor-mediated depolarization in the anterodorsal thalamus. II. Involvement of the hyperpolarization-activated current I(h). J Pharmacol Exp Ther. 2001 PubMed
13. de las Casas-Engel M, Domínguez-Soto A, Sierra-Filardi E, Bragado R, Nieto C, Puig-Kroger A et al. Serotonin skews human macrophage polarization through HTR 2B and HTR 7. J Immunol. 2013 doi:10.4049/jimmunol.1201133 PubMed
14. Dogrul A, Seyrek M. Systemic morphine produce antinociception mediated by spinal 5-HT 7 , but not 5-HT 1A and 5-HT 2 receptors in the spinal cord. Br J Pharmacol. 2006 doi:10.1038/sj.bjp.0706854 PubMed
15. Domínguez-Soto Á, Usategui A, Las Casas-Engel MD, Simón-Fuentes M, Nieto C, Cuevas VD et al. Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis. Sci Rep. 2017 doi:10.1038/s41598-017-15348-y PubMed
16. Errico M, Crozier RA, Plummer MR, Cowen DS. 5-HT7 receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons. Neuroscience. 2001 doi:10.1016/S0306-4522(00)00460-7 PubMed
17. Gill CH, Soffin EM, Hagan JJ, Davies CH. 5-HT7 receptors modulate synchronized network activity in rat hippocampus. Neuropharmacology. 2002 doi:10.1016/S0028-3908(01)00149-6 PubMed
18. Guseva D, Holst K, Kaune B, Meier M, Keubler L, Glage S et al. Serotonin 5-HT7 receptor is critically involved in acute and chronic inflammation of the gastrointestinal tract. Inflamm Bowel Dis. 2014 doi:10.1097/MIB.0000000000000150 PubMed
19. Guseva D, Wirth A, Ponimaskin E. Cellular mechanisms of the 5-HT7 receptor-mediated signaling. Front Behav Neurosci. 2014 doi:10.3389/fnbeh.2014.00306 PubMed
20. Hashemi-Firouzi N, Komaki A, Soleimani Asl S, Shahidi S. The effects of the 5-HT7 receptor on hippocampal long-term potentiation and apoptosis in a rat model of Alzheimer’s disease. Brain Res Bull. 2017 doi:10.1016/j.brainresbull.2017.10.004 PubMed
21. Hedlund P, Sutcliffe J. Functional, molecular and pharmacological advances in 5-HT receptor research. Trends Pharmacol Sci. 2004 doi:10.1016/j.tips.2004.07.002 PubMed
22. Herr N, Bode C, Duerschmied D. The effects of serotonin in immune cells. Front Cardiovasc Med. 2017 doi:10.3389/fcvm.2017.00048 PubMed
23. Holmes Clive, Butchart Joe. Systemic inflammation and Alzheimer's disease. Biochemical Society Transactions. 2011 doi:10.1042/BST0390898 PubMed
24. Holst K, Guseva D, Schindler S, Sixt M, Braun A, Chopra H et al. The serotonin receptor 5-HT7R regulates the morphology and migratory properties of dendritic cells. J Cell Sci. 2015 doi:10.1242/jcs.167999 PubMed
25. Horisawa T, Ishiyama T, Ono M, Ishibashi T, Taiji M. Binding of lurasidone, a novel antipsychotic, to rat 5-HT7 receptor: analysis by [3H]SB-269970 autoradiography. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013 doi:10.1016/j.pnpbp.2012.08.005 PubMed
26. Iceta R, Mesonero JE, Aramayona JJ, Alcalde AI. Expression of 5-HT1A and 5-HT7 receptors in caco-2 cells and their role in the regulation of serotonin transporter activity. J Physiol Pharmacol. 2009 PubMed
27. Idzko M, Panther E, Stratz C, Müller T, Bayer H, Zissel G et al. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. 2004 doi:10.4049/jimmunol.172.10.6011 PubMed
28. Jähnichen S, Glusa E, Pertz HH. Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs. Naunyn Schmiedeberg's Arch Pharmacol. 2005 doi:10.1007/s00210-004-1006-6 PubMed
29. Jasper JR, Kosaka A, Chang DJ, Eglen RM. Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT 7 receptor (h5-HT 7(b) ). Br J Pharmacol. 1997 doi:10.1038/sj.bjp.0701336 PubMed
30. Johnson-Farley NN, Kertesy SB, Dubyak GR, Cowen DS. Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells. J Neurochem. 2005 doi:10.1111/j.1471-4159.2004.02832.x PubMed
31. Kim JJ, Bridle BW, Ghia J-E, Wang H, Syed SN, Manocha MM et al. Targeted Inhibition of Serotonin Type 7 (5-HT 7 ) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation. J Immunol. 2013 doi:10.4049/jimmunol.1201887 PubMed
32. Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke HWGM, Kettenmann H. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun. 2012 doi:10.1016/j.bbi.2011.12.002 PubMed
33. Kvachnina E. 5-HT7 receptor is coupled to G subunits of Heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J Neurosci. 2005 doi:10.1523/JNEUROSCI.1790-05.2005 PubMed
34. León-Ponte M, Ahern GP, O’Connell PJ. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood. 2007 doi:10.1182/blood-2006-10-052787 PubMed
35. Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018 doi:10.1038/nri.2017.125 PubMed
36. Liu H, Irving HR, Coupar IM. Expression patterns of 5-HT7 receptor isoforms in the rat digestive tract. Life Sci. 2001 doi:10.1016/S0024-3205(01)01318-2 PubMed
37. Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA et al. A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron. 1993 doi:10.1016/0896-6273(93)90149-L PubMed
38. Mahé C, Loetscher E, Dev KK, Bobirnac I, Otten U, Schoeffter P. Serotonin 5-HT7 receptors coupled to induction of interleukin-6 in human microglial MC-3 cells. Neuropharmacology. 2005 doi:10.1016/j.neuropharm.2005.01.025 PubMed
39. Müller T, Dürk T, Blumenthal B, Grimm M, Cicko S, Panther E et al. 5-hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of dendritic cells in vitro and in vivo. PLoS One. 2009 doi:10.1371/journal.pone.0006453 PubMed
40. Nilsson T, Longmore J, Shaw D, Pantev E, Bard JA, Branchek T et al. Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol. 1999 doi:10.1016/S0014-2999(99)00114-4 PubMed
41. Peroutka SJ, Snyder SH. Two distinct serotonin receptors: regional variations in receptor binding in mammalian brain. Brain Res. 1981 doi:10.1016/0006-8993(81)90562-X PubMed
42. Polat B, Halici Z, Cadirci E, Karakus E, Bayir Y, Albayrak A et al. Liver 5-HT7 receptors: a novel regulator target of fibrosis and inflammation-induced chronic liver injury in vivo and in vitro. Int Immunopharmacol. 2017 doi:10.1016/j.intimp.2016.12.023 PubMed
43. Querfurth HW, Laferla FM. Alzheimer’s disease. 2018 doi:10.1056/NEJMra0909142 PubMed
44. Quintero-Villegas A, Álvarez-Manzo HS, Bernal-Mondragón C, Guevara-Guzmám R, Valenzuela-Almada MOA. SciFed journal of Alzheimer’s and dementia. SF J Alzh Dement. 2018
45. Rapalli A, Bertoni S, Arcaro V, Saccani F, Grandi A, Vivo V, Cantoni AM, Barocelli E. Dual role of endogenous serotonin in 2,4,6-Trinitrobenzene sulfonic acid-induced colitis. Front Pharmacol. 2016;7. 10.3389/fphar.2016.00068.10.3389/fphar.2016.00068PMC480216627047383 doi:10.3389/fphar.2016.00068 PubMed
46. Rapport MM, Green AA, Page IH. Partial purification of the vasoconstrictor in beef serum. J Biol Chem. 1948 PubMed
47. Renner U., Zeug A., Woehler A., Niebert M., Dityatev A., Dityateva G. et al. Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. Journal of Cell Science. 2012 doi:10.1242/jcs.101337 PubMed
48. Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM et al. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci U S A. 1993 doi:10.1073/pnas.90.18.8547 PubMed
49. Ruddell RG, Oakley F, Hussain Z, Yeung I, Bryan-Lluka LJ, Ramm GA et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol. 2006 doi:10.2353/ajpath.2006.050767 PubMed
50. Russo A, Pellitteri R, Monaco S, Romeo R, Stanzani S. “In vitro” postnatal expression of 5-HT7 receptors in the rat hypothalamus: an immunohistochemical analysis. Dev Brain Res. 2005 doi:10.1016/j.devbrainres.2004.11.002 PubMed
51. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017 doi:10.1038/nm.4397 PubMed
52. Sankowski R, Mader S, Valdés-Ferrer SI. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci. 2015 doi:10.3389/fncel.2015.00028 PubMed
53. Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DR. Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. J Biol Chem. 1993 PubMed
54. Soga F, Katoh N, Inoue T, Kishimoto S. Serotonin activates human monocytes and prevents apoptosis. J Invest Dermatol. 2007 doi:10.1038/sj.jid.5700824 PubMed
55. Speranza L, Chambery A, Di Domenico M, Crispino M, Severino V, Volpicelli F et al. The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways. Neuropharmacology. 2013 doi:10.1016/j.neuropharm.2012.10.026 PubMed
56. Stefulj J, Jernej B, Cicin-Sain L, Rinner I, Schauenstein K. mRNA expression of serotonin receptors in cells of the immune tissues of the rat. Brain Behav Immun. 2000 doi:10.1006/brbi.1999.0579 PubMed
57. Strasser B, Gostner JM, Fuchs D. Mood, food, and cognition: role of tryptophan and serotonin. Curr Opin Clin Nutr Metab Care. 2016 doi:10.1097/MCO.0000000000000237 PubMed
58. Svejda B, Kidd M, Timberlake A, Harry K, Kazberouk A, Schimmack S et al. Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors. Cancer Sci. 2013 doi:10.1111/cas.12174 PubMed
59. Tawfik MK, Makary S. 5-HT7 receptor antagonism (SB-269970) attenuates bleomycin-induced pulmonary fibrosis in rats via downregulating oxidative burden and inflammatory cascades and ameliorating collagen deposition: comparison to terguride. Eur J Pharmacol. 2017 doi:10.1016/j.ejphar.2017.08.014 PubMed
60. Terrón JA, Falcón-Neri A. Pharmacological evidence for the 5-HT7 receptor mediating smooth muscle relaxation in canine cerebral arteries. Br J Pharmacol. 1999 doi:10.1038/sj.bjp.0702580 PubMed
61. Thomas D, Hagan J. 5-HT7 Receptors. Curr Drug Target -CNS Neurol Disord. 2004 doi:10.2174/1568007043482633 PubMed
62. Tokarski K, Zahorodna A, Bobula B, Hess G. 5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons. Brain Res. 2003 doi:10.1016/j.brainres.2003.09.015 PubMed
63. Urbina M, Arroyo R, Lima L. 5-HT7 receptors and tryptophan hydroxylase in Lymphoctytes of rats: mitogen activation, physical restraint or treatment with reserpine. Neuroimmunomodulation. 2014 doi:10.1159/000357148 PubMed
64. Valdés-Ferrer SI. The challenges of long-term sepsis survivors: when surviving is just the beginning. Rev Investig Clin. 2014 PubMed
65. Valdés‐Ferrer S. I., Rosas‐Ballina M., Olofsson P. S., Lu B., Dancho M. E., Ochani M. et al. Expression of Concern: HMGB 1 mediates splenomegaly and expansion of splenic CD 11b+ L y‐6 C high inflammatory monocytes in murine sepsis survivors. Journal of Internal Medicine. 2013 doi:10.1111/joim.12104 PubMed
66. Vanhoenacker P, Haegeman G, Leysen JE. 5-HT 7 receptors: current knowledge and future prospects. Trends Pharmacol Sci. 2000 doi:10.1016/S0165-6147(99)01432-7 PubMed
67. Wolf SA, Boddeke HWGM, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol. 2017 doi:10.1146/annurev-physiol-022516-034406 PubMed
68. Wu H, Denna TH, Storkersen JN, Gerriets VA. Beyond a neurotransmitter: the role of serotonin in inflammation and immunity. Pharmacol Res. 2019 doi:10.1016/j.phrs.2018.06.015 PubMed
69. Yaakob NS, Chinkwo KA, Chetty N, Coupar IM, Irving HR. Distribution of 5-HT 3 , 5-HT 4 , and 5-HT 7 Receptors Along the Human Colon. J Neurogastroenterol Motil. 2015 doi:10.5056/jnm14157 PubMed
70. Zhou X, Zhang R, Zhang S, Wu J, Sun X. Activation of 5-HT1A receptors promotes retinal ganglion cell function by inhibiting the cAMP-PKA pathway to modulate presynaptic GABA release in chronic glaucoma. J Neurosci. 2019 doi:10.1523/JNEUROSCI.1685-18.2018 PubMed