Serotonin skews human macrophage polarization through HTR2B and HTR7.
Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) 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 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT(2B) and 5HT(7) 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. 5HT(2B) 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 5HT(2B) and 5HT(7), whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain.
Mateo
M
de las Casas-Engel
Angeles
A
Domínguez-Soto
Elena
E
Sierra-Filardi
Rafael
R
Bragado
Concha
C
Nieto
Amaya
A
Puig-Kroger
Rafael
R
Samaniego
Mabel
M
Loza
María Teresa
MT
Corcuera
Fernando
F
Gómez-Aguado
Matilde
M
Bustos
Paloma
P
Sánchez-Mateos
Angel L
AL
Corbí
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides; D008156:Luciferases; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000276:immunology*; D011985:Receptors, Serotonin / Q000235:genetics / Q000276:immunology*; D012701:Serotonin / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D015415:Biomarkers; D008070:Lipopolysaccharides; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D016753:Interleukin-10; D012701:Serotonin; D008156:Luciferases