Long-Term Effects of DMPO on Switching Macrophage?s Phenotype in the Obese Adiopose Tissue

MARCOS D MUNOZ; MARIA C DELLA VEDOVA; SERGIO E ALVAREZ; ROBERT A FLOYD; SANDRA E GOMEZ MEJIBA; DARIO C RAMIREZ

Congreso; SFRBM; 2016

">99Long-Term Effects of DMPO on SwitchingMacrophage?s Phenotype in the Obese AdioposeTissueMarcos D Munoz1, Maria C Della Vedova1, Sergio E Alvarez1, Robert AFloyd2, Sandra E Gomez Mejiba1, and Dario C Ramirez11Conicet-Unsl, San Luis, Argentina, 2 OMRFf, Oklahoma City, USAMacrophages are tissue cells from the innate-immune systemwhere they play a number of homeostatic and defense functions.Inside the tissues and under tissue-specific microenvironmentalpressures monocytes are recruited and differentiated to specificphenotypes. This phenotype is a consequence of the expression ofspecific genes that are under the control of one or moretranscription factors. In this context, inflammatory phenotype ofadipose tissue (AT) macrophages (ATM-M1) is responsible foradipose tissue oxidative stress and inflammation mediators thatreduce whole-body insulin sensitivity and cause a number ofmetabolic abnormalities-associated to obesity. Intratrachealinstillation of the nitrone spin trap 5,5-dimethyl-1-pirroline N-oxide(DMPO) to diet-induced obese-mice reduced markers of AToxidative stress and inflammation, reduced serum concentration ofinflammatory cytokines and improved insulin sensitivity. Thus wehypothesized that DMPO may produce transcripcional effects inmacrophages at the AT and maybe other tissues. To approach thishypothesis we determined the transcripcional effects of DMPO inRAW264.7 cells after 6h incubation and with or withoutlipopolysaccharide (LPS) to model transcriptional profile of ATM.Microarray data showed that LPS caused an M1-transcriptionalpattern, whereas DMPO reduced these changes. Remarkableeffects were observed in the expression of IRF-7 and PPAR-d,master regulators of genes that determine M1 and M2 macrophagephenotype. LPS induced IRF-7, but reduced PPARd expression;whereas DMPO reduced IRF-7, but induced PPAR-d expression.Taking together our data suggest that DMPO may serve as astructural platform for the design of novel compounds to reduce ATinflammation and, thus other inflammatory abnormalitiesassociated to obesity, such as insulin resistance and metabolicsyndrome.Supported by PROICO 2-3214 & PICT-2014-3369 (to DCR),PROICO 10-0414 (To SEGM) and PIP2015-2017-112215-0100603CO (To DCR, SEGM & SEGM).doi: 10.1016/j.freeradbiomed.2016.10.140