title: IL-6 promotes M2 macrophage polarization by modulating purinergic signaling and regulates the lethal release of nitric oxide during Trypanosoma cruzi infection.
abstract: 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-1β 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-1β 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-1β inhibition and determines the establishment of an M2 macrophage profile within infected heart tissue.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: lsanmarco@fcq.unc.edu.ar.
authors.forename: Liliana M
authors.initials: LM
authors.lastname: Sanmarco
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: nponce@fcq.unc.edu.ar.
authors.forename: Nicolás E
authors.initials: NE
authors.lastname: Ponce
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo, Córdoba, Argentina. Electronic address: lau_visconti81@yahoo.com.ar.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Visconti
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: neberhardt@fcq.unc.edu.ar.
authors.forename: Natalia
authors.initials: N
authors.lastname: Eberhardt
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: mgtheumer@fcq.unc.edu.ar.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Theumer
authors.affiliation: Hospital Nuestra Señora de la Misericordia del Nuevo Siglo, Córdoba, Argentina. Electronic address: angelminguez04@yahoo.com.ar.
authors.forename: Ángel R
authors.initials: ÁR
authors.lastname: Minguez
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: paoki@fcq.unc.edu.ar.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Aoki
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000276:immunology*; D000818:Animals; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology*
chemical_list: D015850:Interleukin-6; C577686:interleukin-6, mouse; D009569:Nitric Oxide; D000255:Adenosine Triphosphate
keywords: CD39; CD73; Human monocytes; Innate immunity