Serotonin promotes the acquisition of an anti-inflammatory and pro-fibrotic profile in human macrophages via engagement of HTR7

Peripheral serotonin (5-hydroxytryptamine, 5HT) regulates cell growth and differentiation in numerous cell types through engagement of seven types of cell surface receptors (HTR1-7). Deregulated 5HT/HTR levels contribute to pathology in chronic inflammatory diseases, with macrophages being relevant targets for the physio-pathological effects of 5HT. In fact, 5HT skews human macrophage polarization through engagement of HTR2B and HTR7 receptors. We now report that 5HT primes macrophages for reduced pro-inflammatory cytokine production and IFN type I-mediated signalling, and promotes an anti-inflammatory and pro-fibrotic gene signature in human macrophages. The acquisition of the 5HT-dependent gene profile primarily depends on the HTR7 receptor and HTR7-initiated PKA-dependent signaling. In line with the transcriptional results, 5HT upregulates TGFb1 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 5HT is primarily mediated through the HTR7-PKA axis, and that HTR7 contributes to pathology in fibrotic diseases. Macrophages were differentiated from peripheral blood monocytes from 3 healthy donors with M-CSF (M-MØ). Before treatment with 5HT, M-MØ macrophages were maintained in serum-free medium for 48 hours. Macrophages were untreated or 5HT-treated (10 uM) during 6 hours and global gene expression was analysed.