[Nle4, D-Phe7]-α-MSH Inhibits Toll-Like Receptor (TLR)2- and TLR4-Induced Microglial Activation and Promotes a M2-Like Phenotype

• Published in: PloS one 2016-06, Vol.11 (6), p.e0158564-e0158564
• Main Authors: Carniglia, Lila, Ramírez, Delia, Durand, Daniela, Saba, Julieta, Caruso, Carla, Lasaga, Mercedes
• Format: Article
• Language: English
• Subjects: Activation; alpha-MSH - analogs & derivatives; alpha-MSH - pharmacology; Animals; Biology and Life Sciences; Biomedical research; Brain research; Cells, Cultured; Cytokines; Cytoplasm; Disease; Disorders; Genotype & phenotype; HMGB1 protein; Immune system; Immunomodulation; Inflammation; Interleukin 10; Interleukin-10 - metabolism; Ischemia; Kinases; Lipopeptides - pharmacology; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Medicine; Medicine and Health Sciences; Melanocortin; Melanocortin MC4 receptors; Microglia; Microglia - drug effects; Microglia - metabolism; Microglial cells; Neurodegeneration; Neuronal-glial interactions; NF-κB protein; Nuclear transport; Peroxisome proliferator-activated receptors; Phagocytes; Phenotypes; Proteins; Rats; Rodents; TLR2 protein; TLR4 protein; TNF inhibitors; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Translocation; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158564

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.