title: [Nle4, D-Phe7]-α-MSH Inhibits Toll-Like Receptor (TLR)2- and TLR4-Induced Microglial Activation and Promotes a M2-Like Phenotype.
abstract: α-melanocyte stimulating hormone (α-MSH) is an anti-inflammatory peptide, proved to be beneficial in many neuroinflammatory disorders acting through melanocortin receptor 4 (MC4R). We previously determined that rat microglial cells express MC4R and that NDP-MSH, an analog of α-MSH, induces PPAR-γ expression and IL-10 release in these cells. Given the great importance of modulation of glial activation in neuroinflammatory disorders, we tested the ability of NDP-MSH to shape microglial phenotype and to modulate Toll-like receptor (TLR)-mediated inflammatory responses. Primary rat cultured microglia were stimulated with NDP-MSH followed by the TLR2 agonist Pam3CSK4 or the TLR4 agonist LPS. NDP-MSH alone induced expression of the M2a/M2c marker Ag1 and reduced expression of the M2b marker Il-4rα and of the LPS receptor Tlr4. Nuclear translocation of NF-κB subunits p65 and c-Rel was induced by LPS and these effects were partially prevented by NDP-MSH. NDP-MSH reduced LPS- and Pam3CSK4-induced TNF-α release but did not affect TLR-induced IL-10 release. Also, NDP-MSH inhibited TLR2-induced HMGB1 translocation from nucleus to cytoplasm and TLR2-induced phagocytic activity. Our data show that NDP-MSH inhibits TLR2- and TLR4-mediated proinflammatory mechanisms and promotes microglial M2-like polarization, supporting melanocortins as useful tools for shaping microglial activation towards an alternative immunomodulatory phenotype.
authors.affiliation: Institute of Biomedical Research (INBIOMED -UBA- CONICET), School of Medicine, University of Buenos Aires, Buenos Aires, 1121, Argentina.
authors.forename: Lila
authors.initials: L
authors.lastname: Carniglia
authors.affiliation: Institute of Biomedical Research (INBIOMED -UBA- CONICET), School of Medicine, University of Buenos Aires, Buenos Aires, 1121, Argentina.
authors.forename: Delia
authors.initials: D
authors.lastname: Ramírez
authors.affiliation: Institute of Biomedical Research (INBIOMED -UBA- CONICET), School of Medicine, University of Buenos Aires, Buenos Aires, 1121, Argentina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Durand
authors.affiliation: Institute of Biomedical Research (INBIOMED -UBA- CONICET), School of Medicine, University of Buenos Aires, Buenos Aires, 1121, Argentina.
authors.forename: Julieta
authors.initials: J
authors.lastname: Saba
authors.affiliation: Institute of Biomedical Research (INBIOMED -UBA- CONICET), School of Medicine, University of Buenos Aires, Buenos Aires, 1121, Argentina.
authors.forename: Carla
authors.initials: C
authors.lastname: Caruso
authors.affiliation: Institute of Biomedical Research (INBIOMED -UBA- CONICET), School of Medicine, University of Buenos Aires, Buenos Aires, 1121, Argentina.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lasaga
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016753:Interleukin-10 / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-