Long-term effects of DMPO: Switching of macrophage?s phenotypes to reduce adipose tissue inflammation in obesity

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

Congreso; SAIC 2016; 2016

Macrophages are tissue cells from the innate-immune system where they play a number of homeostatic and defense functions. Inside the tissues and under tissue-specific microenvironmental pressures monocytes are recruited and differentiated to specific phenotypes. This phenotype is a consequence of the expression of specific genes that are under the control of one or more transcription factors. In this context, inflammatory phenotype of adipose tissue (AT) macrophages (ATM-M1) is responsible for adipose tissue oxidative stress and inflammation mediators that reduce whole-body insulin sensitivity and cause a number of metabolic abnormalities-associated to obesity. Intratracheal instillation of the nitrone spin trap 5,5-dimethyl-1-pirroline N-oxide (DMPO) to diet-induced obese-mice reduced markers of AT oxidative stress and inflammation, reduced serum concentration of inflammatory cytokines and improved insulin sensitivity. Thus we hypothesized that DMPO may produce transcripcional effects in macrophages at the AT and maybe other tissues. To approach this hypothesis we determined the transcripcional effects of DMPO in RAW264.7 cells after 6h incubation and with or without lipopolysaccharide (LPS) to model transcriptional profile of ATM. Microarray data showed that LPS caused an M1-transcriptional pattern, whereas DMPO inhibited these changes. Remarkable effects were observed in the expression of IRF-7 and PPAR-, master regulators of genes that determine M1 and M2 macrophage phenotype. LPS induced IRF-7, but reduced PPAR- expression; whereas DMPO reduced IRF-7, but induced PPAR- expression. Taking together our data suggest that DMPO may serve as a structural platform for the design of novel compounds to reduce AT inflammation and, thus other inflammatory abnormalities-associated to obesity, such as insulin resistance and metabolic syndrome. Supported by PROICO 2-3214 & PICT-2014-3369 (to DCR), PROICO 10-0414 (To SEGM) and PIP2015-2017-112215-0100603CO (To DCR, SEA & SEGM).