[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: Lila Carniglia, Delia Ramírez, Daniela Durand, Julieta Saba, Carla Caruso, Mercedes Lasaga
• Journal: PloS one (PLoS One) Vol. 11 Issue 6 Pg. e0158564 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27359332 (Publication Type: Journal Article)

Chemical References

• Lipopeptides
• Lipopolysaccharides
• Pam(3)CSK(4) peptide
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Interleukin-10
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-

Topics

• Animals
• Cells, Cultured
• Interleukin-10 (metabolism)
• Lipopeptides (pharmacology)
• Lipopolysaccharides (pharmacology)
• Microglia (drug effects, metabolism)
• Rats
• Toll-Like Receptor 2 (agonists, metabolism)
• Toll-Like Receptor 4 (agonists, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• alpha-MSH (analogs & derivatives, pharmacology)