Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis

Abstract

Peripheral serotonin (5-hydroxytryptamine, 5-HT) regulates cell growth and differentiation in numerous cell types through engagement of seven types of cell surface receptors (HTR1–7). Deregulated 5-HT/HTR levels contribute to pathology in chronic inflammatory diseases, with macrophages being relevant targets for the physio-pathological effects of 5-HT. In fact, 5-HT skews human macrophage polarization through engagement of 5-HT2BR and 5-HT7R receptors. We now report that 5-HT primes macrophages for reduced pro-inflammatory cytokine production and IFN type I-mediated signaling, and promotes an anti-inflammatory and pro-fibrotic gene signature in human macrophages. The acquisition of the 5-HT-dependent gene profile primarily depends on the 5-HT7R receptor and 5-HT7R-initiated PKA-dependent signaling. In line with the transcriptional results, 5-HT upregulates TGFβ1 production by human macrophages in an HTR7- and PKA-dependent manner, whereas the absence of Htr7 in vivo results in diminished macrophage infiltration and collagen deposition in a mouse model of skin fibrosis. Our results indicate that the anti-inflammatory and pro-fibrotic activity of 5-HT is primarily mediated through the 5-HT7R-PKA axis, and that 5-HT7R contributes to pathology in fibrotic diseases.

5-HT2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation

“…The transcriptional effects of BW723C86 on human macrophages differ considerably from those triggered by 5-HT, most of which can be mimicked or abrogated by 5-HT 7 agonists or antagonists, respectively 39 . Thus, although 5-HT 2B and 5-HT 7 are preferentially expressed by anti-inflammatory human macrophages 40 and promote a pro-fibrotic phenotype 19,39,47,114,115 , their individual engagement leads to different transcriptional outcomes, with AhR-activating ability being restricted to 5-HT 2B . The failure of 5-HT to activate AhR in human macrophages might rely on the fact that 5-HT can bind to both 5-HT 2B and 5-HT 7 , and can therefore initiate intracellular signaling from both receptors.…”

“…The failure of 5-HT to activate AhR in human macrophages might rely on the fact that 5-HT can bind to both 5-HT 2B and 5-HT 7 , and can therefore initiate intracellular signaling from both receptors. Ligation of 5-HT 7 by 5-HT triggers protein kinase A (PKA)-dependent signaling and transcription in macrophages 39 and other cell types 116 , and results in the expression of PKA-regulated genes like PDE2A 39 . Since PKA activation (or increased cAMP levels) represses AhR-dependent gene expression 117,118 , it is therefore possible that the binding of 5-HT to 5-HT 7 , and the resulting PKA activation 39,116 , might prevent the activation of AhR secondary to 5-HT binding to 5-HT 2B .…”

“…Ligation of 5-HT 7 by 5-HT triggers protein kinase A (PKA)-dependent signaling and transcription in macrophages 39 and other cell types 116 , and results in the expression of PKA-regulated genes like PDE2A 39 . Since PKA activation (or increased cAMP levels) represses AhR-dependent gene expression 117,118 , it is therefore possible that the binding of 5-HT to 5-HT 7 , and the resulting PKA activation 39,116 , might prevent the activation of AhR secondary to 5-HT binding to 5-HT 2B . In line with this hypothesis, it is worth noting that PDE2A gene expression in macrophages is greatly upregulated after 5-HT binding to 5-HT 7 39 , and that PDE2A interaction with the immunophilin-like protein XAP2 (a member of the molecular complex that retains unliganded AhR in the cytoplasm) inhibits dioxin-induced AhR nuclear translocation and transcription in hepatocytes 119 .…”

“…Not surprisingly, macrophage effector functions are directly modulated by 5-HT 17,22,26,35,36 , and also by Selective Serotonin Reuptake Inhibitors (SSRI) 37,38 . We have previously demonstrated that 5-HT 7 is the major mediator of the anti-inflammatory actions of 5-HT on human macrophages 39 and that both 5-HT 2B and 5-HT 7 contribute to the maintenance of the anti-inflammatory state of M-CSF-dependent human macrophages 40 .…”

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

“…Treatment of melanoma cell lines with TM did not alter cAMP levels (Additional file 1: Figure S2A). The expression of genes that have been previously shown to be upregulated upon serotonin (5-HT) treatment through PKA signaling, PDE2A, MET, TREM1, THBS1, SERPINB2 and S1PR1 [19] was not changed following TM treatment (Additional file 1: Figure S2B). As expected, with the lack of change in cAMP levels, there was no significant increase in the phosphorylation of the cAMP response element binding protein (CREB) in RPMI, B16F10, A375, SK-MEL-24, MeWo cells although p-CREB was increased in SH4 and MEL-JUSO cells ( Fig.…”