Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1863, Issue 4, Pages 857-869Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2017.01.006
Keywords
CD39; CD73; Human monocytes; Innate immunity
Funding
- Secretaria de Ciencia y Tecnologia
- Universidad Nacional de Cordoba [05/C642]
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [PICT 2013-2885]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) [PIP 11220120100620]
- Ministerio de Ciencia y Tecnologia
- Gobierno de la Provincia de Cordoba
- Secretaria de Ciencia y Tecnologia [1143/10]
- CONICET for the fellowships
- Fundacion Florencio Fiorini and ANPCyT-FONCyT respectively
Ask authors/readers for more resources
The production of nitric oxide (NO) is a key defense mechanism against intracellular pathogens but it must be tightly controlled in order to avoid excessive detrimental oxidative stress. In this study we described a novel mechanism through which interleukin (IL)-6 mediates the regulation of NO release induced in response to Trypanosoma cruzi infection. Using a murine model of Chagas disease, we found that, in contrast to C57BL/6 wild type (WT) mice, IL-6-deficient (IL6KO) mice exhibited a dramatic increase in plasma NO levels concomitant with a significantly higher amount of circulating IL-1 beta and 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-1 beta and in macrophages deficient in the NLRP3 inflammasome. In accordance, 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. The deleterious effects of high NO production-induced oxidative stress were evidenced by enhanced cardiac malondialdehyde levels, myocardial cell death and mortality. The survival rate was improved by the treatment of IL-6-deficient mice with a NO production-specific inhibitor. Our data revealed that IL-6 regulates the excessive release of NO through IL-1 beta inhibition and determines the establishment of an M2 macrophage profile within infected heart tissue. (C) 2017 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available