The nitrone spin trap DMPO switches macrophage towards an M2-like anti-inflammatory phenotype

MUÑOZ MD,; ALVAREZ, S.; GOMEZ-MEJIBA S.E; RAMIREZ D.C,

ATLANTA

Congreso; SFRBM; 2015

The search for mechanism-based therapeutics against chronicinflammation (CI) is a highly desired focus of pharmaceuticalindustries. The switch of macrophages phenotype from a normalM2-like towards an inflammatory M1-like phenotype is known toplay an important pathogenic role in a number of CI diseases.Previously we found that the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) besides being an efficient and cellpermeable spin trap can produce anti-inflammatory and insulinsensitizing effects in models of diet-induced obesity. Although,many of the spin trapping properties of DMPO have beenextensively investigated, the information regardingpharmacological effects of this spin trap is more limited. Hereinwe aimed at digging into the molecular mechanism by whichDMPO reduce inflammatory activation of macrophages. Toapproach this aim we used a well known model of RAW264.7-macrophage-like cells treated with 1 ng/ml lipopolysaccharide(LPS) with or without 50 mM DMPO and found that DMPOdamped LPS-induced activation of inflammatory geneexpression and cytokine production. Trasncriptomics(microarray), proteomics (iTRAQ) and Ingenuity Pathwayanalyses suggest that DMPO damped LPS-distinctivetranscriptome profile of inflammatory mediators by switchingtranscription factors involved its cell response. LPS activatesNF-kB and IRF-7 signaling pathways that cause an M1-likephenotype of macrophages. When these cells are pretreatedwith DMPO, it caused signaling/transcriptome/proteomechanges to give a typical M2-like phenotype that is resistant toLPS-induced activation. DMPO triggers an anti-inflammatoryand antioxidant-PPAR-d/Nrf-2-dependent M2-phenotype. Takingtogether our data suggest that the anti-inflammatory effects ofDMPO on macrophage is due to a switch on signaling,transcriptome and proteome towards an M2-like phenotype.PICT-2014-3369, PROICO-2-3214 and PROICO10-0414.