Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

Abstract

Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT1–7) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization–associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT7 mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT2B and 5HT7 receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT2B was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT2B and 5HT7, whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…First, Htr2b expression has been detected in newborn brain microglia [40] although it remains low in basal conditions [12,8,7,31]. Htr2b is also highly expressed in peripheral macrophages [14]. Htr2b mRNA expression was restricted to CD11b-positive cells purified from spinal cord and brainstem, thus originating from mononuclear phagocytes, either microglia or infiltrating monocytes.…”

“…5-HT 2B R is expressed in microglia in the CNS [40], with expression in other cell types including brain serotonin neurons [16]. In human peripheral macrophages, 5-HT 2B R mediates the response to serotonin by skewing macrophages to a M2, anti-inflammatory, phenotype [14]. More relevant to ALS, we showed that 5-HT 2B R is the major serotonin receptor expressed on perinatal microglia and regulates chemotaxis of microglial processes in response to serotonin [40].…”

“…Since 5-HT 2B R is expressed in microglia and peripheral macrophages [14,40], increased 5-HT 2B R expression could reflect microglial activation and/or infiltrated monocyte activation. To address this question, we purified CD11b positive cells from late stage SOD1(G86R) mice using magnetic bead cell sorting, followed by RT-qPCR.…”

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

“…Data are representative of three separate experiments. recently that serotonin specifically modulates macrophage polarization by promoting acquisition of an anti-inflammatory state, which is characterized by inhibition of LPS-induced release of IL-12 and TNF-a by M-CSF-treated (M2) macrophages and downregulation of genes associated with an M1 phenotype (including MMP12 and CCR2) (36,37). The differential expression of 5HT2B and 5HT7 serotonin receptors on M2 and M1 macrophages may be important for determining the effects of serotonin in monocyte subsets (37).…”

Distribution of 5-HT3, 5-HT4, and 5-HT7Receptors Along the Human Colon

“…5-HT 7 receptors are also found on macrophages and have been implicated as a potential target for treating intestinal inflammatory disorders. 59,60 Serotonin induces desensitization (tachyphylaxis) at different rates and magnitudes in different tissues and this is the case with 5-HT 4 receptor agonists as highlighted by prucalopride desensitizing pig atrium but not pig stomach 5-HT 4 receptors. 61 Different GRKs are associated with 5-HT 4 receptor desensitization depending on the tissue type in the rat and significantly these GRKs are not necessarily those predicted by studies using recombinant proteins expressed in cell culture.…”