The Nitrone Spin Trap DMPO switches macrophages toward and M2-like anti-inflammatory phenotype

MUNOZ M; ALVAREZ SE; GOMEZ MEJIBA, S; RAMIREZ, DC

Boston

Congreso; Society for redox Biology and Medicine 2015; 2015

The search for mechanism-based therapeutics against chronic inflammation (CI) is a highly desired focus of pharmaceutical industries. The switch of macrophages phenotype from a normal M2-like towards an inflammatory M1-like phenotype is known to play 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 cell permeable spin trap can produce anti-inflammatory and insulin sensitizing effects in models of diet-induced obesity.Although,many of the spin trapping properties of DMPO have been extensively investigated, the information regarding pharmacological effects of this spin trap is more limited. Herein we aimed at digging into the molecular mechanism by which DMPO reduce inflammatory activation of macrophages. To approach this aim we used a well-known model of RAW264.7macrophage-like cells treated with 1 ng/ml lipopolysaccharide (LPS) with or without 50 mM DMPOand found tha tDMPO damped LPS-induced activation of inflammatory gene expression and cytokine production.Trasncriptomics (microarray), proteomics (iTRAQ)and Ingenuity Pathway analyses suggest that DMPO damped LPS-distinctive transcriptome profile of inflammatory mediators by switching transcription factors involved its cell response. LPS activates NF-kB and IRF-signaling pathways that cause an M1-like phenotype of macrophages. When these cells are pretreated with DMPO, it caused signaling/transcriptome/proteome changes to give a typical M2-like phenotype that is resistant to LPS-induced activation. DMPO triggers an anti-inflammatory and antioxidant-PPARd/Nrf-2-dependent M2-phenotype. Taking together our data suggest that the anti-inflammatory effects of DMPO on macrophage is due to a switch on signaling, transcriptome and proteome towards an M2-like phenotype