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.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter derived from L-tryptophan via a rate-limiting reaction catalyzed by tryptophan hydroxylases (TPH1 in periphery, TPH2 in brain)[1,2]
We have previously demonstrated that human pro-inflammatory and anti-inflammatory macrophages[40,41,42,43] exhibit a distinct profile of 5-HT receptors, and that 5-HT2BR and 5-HT7R shape macrophage effector functions towards the anti-inflammatory side[44]
To dissect the molecular mechanisms underlying the inflammation-modulating action of 5-HT, we undertook the determination of the 5-HT-dependent transcriptome of human macrophages. 5-HT rapidly altered the human macrophage transcriptome towards a growth-promoting, anti-inflammatory and pro-fibrotic gene profile, whose acquisition was dependent on the 5-HT7R -PKA signaling axis
Summary
Ángeles Domínguez-Soto[1], Alicia Usategui[2], Mateo de las Casas-Engel[1], Miriam Simón-Fuentes[1], Concha Nieto1,Víctor D. 5-HT rapidly altered the human macrophage transcriptome towards a growth-promoting, anti-inflammatory and pro-fibrotic gene profile, whose acquisition was dependent on the 5-HT7R -PKA signaling axis. Since the 5-HT7R-PKA axis mediates the expression of the 5-HT-dependent M-MØ transcriptome, we evaluated whether this signaling axis contributes to the inhibitory effect of 5-HT on the LPS-induced production of inflammatory cytokines by M-MØ, which produce undetectable levels of TNFα and IL-12p40 in the absence of stimulation[44]. 5-HT conditions macrophages for a diminished production of pro-inflammatory cytokines primarily via engagement of 5-HT7R and activation of PKA As a whole, this set of results demonstrates that the 5-HT7R-PKA axis mediates the acquisition of the 5-HT-dependent gene and cytokine profile in human macrophages. In line with the transcriptional results in human macrophages, 5-HT7R expression contributes to macrophage accumulation and fibrosis in the bleomycin model of skin fibrosis
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