title: CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy.
abstract: Increasing evidence demonstrates that generation of extracellular adenosine from ATP, which is hydrolyzed by the CD39/CD73 enzyme pair, attenuates the inflammatory response and deactivates macrophage antimicrobial mechanisms. Although CD73 is emerging as a critical pathway and therapeutic target in cardiovascular disorders, the involvement of this ectonucleotidase during myocardial infection has not been explored. Using a murine model of infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy, we observed a sudden switch from the classical M1 macrophage (microbicidal) phenotype toward an alternative M2 (repairing/anti-inflammatory) phenotype that occurred within the myocardium very shortly after BALB/c mice infection. The observed shift in M1/M2 rate correlated with the cardiac cytokine milieu. Considering that parasite persistence within myocardium is a necessary and sufficient condition for the development of the chronic myocarditis, we hypothesized that CD73 activity may counteract cardiac macrophage microbicidal polarization, rendering the local immune response less effective. In fact, a transient treatment with a specific CD73 inhibitor (adenosine 5'-α,β-methylene-diphosphate) enhanced the microbicidal M1 subset predominance, diminished IL-4- and IL-10-producing CD4(+) T cells, promoted a proinflammatory cytokine milieu, and reduced parasite load within the myocardium during the acute phase. As a direct consequence of these events, there was a reduction in serum levels of creatine kinase muscle-brain isoenzyme, a myocardial-specific injury marker, and an improvement in the electrocardiographic characteristics during the chronic phase. Our results demonstrate that this purinergic system drives the myocardial immune response postinfection and harbors a promising potential as a therapeutic target.
authors.affiliation: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina;
authors.forename: Nicolás Eric
authors.identifier: 0000-0002-7052-5086
authors.initials: NE
authors.lastname: Ponce
authors.affiliation: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina;
authors.forename: Liliana Maria
authors.identifier: 0000-0002-2075-8826
authors.initials: LM
authors.lastname: Sanmarco
authors.affiliation: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina;
authors.forename: Natalia
authors.initials: N
authors.lastname: Eberhardt
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias Químicas, Unidad de Investigación y Desarrollo en Tecnología Farmacéutica-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina;
authors.forename: Mónica Cristina
authors.initials: MC
authors.lastname: García
authors.affiliation: Facultad de Ciencias Médicas, Centro de Estudios e Investigación de la Enfermedad de Chagas y Leishmaniasis, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; and.
authors.forename: Héctor Walter
authors.initials: HW
authors.lastname: Rivarola
authors.affiliation: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; Facultad de Ciencias Químicas, UA Área de Ciencias Agrarias, Ingeniería, Ciencias Biológicas y de la salud-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Católica de Córdoba, Córdoba 5000, Argentina.
authors.forename: Roxana Carolina
authors.initials: RC
authors.lastname: Cano
authors.affiliation: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; paoki@fcq.unc.edu.ar.
authors.forename: Maria Pilar
authors.identifier: 0000-0002-6897-7702
authors.initials: MP
authors.lastname: Aoki
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006321:Heart / Q000382:microbiology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015720:5'-Nucleotidase