IL-6 promotes M2 macrophage polarization by modulating purinergic signaling and regulates the lethal release of nitric oxide during Trypanosoma cruziinfection

SANMARCO, LM; PONCE, NE; VISCONTI, LM; EBERHARDT, N; THEUMER, M; MINGUEZ, RA; AOKI, MP

BIOCHIMICA AND BIOPHYSICA ACTA

Elsevier

Año: 2017

0006-3002

The production of nitric oxide (NO) is a key defense mechanism against intracellular pathogens but it must betightly controlled in order to avoid excessive detrimental oxidative stress. In this study we described a novelmechanism through which interleukin (IL)-6 mediates the regulation of NO release induced in response toTrypanosoma cruziinfection. Using a murine model of Chagas disease, we found that, in contrast to C57BL/6wild type (WT) mice, IL-6-deficient (IL6KO) mice exhibited a dramatic increase in plasma NO levels concomitantwith a significantly higher amount of circulating IL-1βand inflammatory monocytes. Studies on mouse macrophages and human monocytes, revealed that IL-6 decreased LPS-induced NO production but this effect was abrogated in the presence of anti-IL-1βand in macrophages deficient in the NLRP3 inflammasome. Inaccordance, while infected WT myocardium exhibited an early shift from microbicidal/M1 to anti-inflammatory/M2 macrophage phenotype, IL6KO cardiac tissue never displayed a dominant M2 macrophage profile that correlated with decreased expression of ATP metabolic machinery and a lower cardiac parasite burden. Thedeleterious effects of high NO production-induced oxidative stress were evidenced by enhanced cardiacmalondialdehyde levels, myocardial cell death and mortality. The survival rate was improved by the treatmentof IL-6-deficient mice with a NO production-specific inhibitor. Our data revealed that IL-6 regulates the excessiverelease of NO through IL-1βinhibition and determines the establishment of an M2 macrophage profile within infected heart tissue