CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

EBERHARDT, N; CANO, RC; PONCE, NE; GARCÍA, MC; AOKI, MP; SANMARCO, LM; RIVAROLA G

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2016

0022-1767

Increasingevidence demonstrate that generation of extracellular adenosine from ATP, whichis hydrolyzed by the CD39/CD73 enzyme pair, attenuates the inflammatoryresponse and deactivates macrophage anti-microbial mechanisms. Although CD73 isemerging as a critical pathway and therapeutic target in cardiovasculardisorders, the involvement of this ectonucleotidase during myocardial infectionhas not been explored. Using a murine model of infection with Trypanosomacruzi, the causal agent of Chagas cardiomyopathy, we observed a sudden switchfrom classical M1 macrophage (microbicidal) phenotype toward alternative M2(repairing/anti-inflammatory) phenotype that occurred within the myocardiumvery shortly after BALB/c mice infection. The observed shift in M1/M2 ratecorrelated with the cardiac cytokine milieu. Considering that parasitepersistence within myocardium is a necessary and sufficient condition for thedevelopment of the chronic myocarditis, we hypothesized that CD73 activity maycounteract cardiac macrophage microbicidal polarization rendering the localimmune response less effective. In fact, a transient treatment with a specificCD73 inhibitor (APCP) enhanced the microbicidal M1 subset predominance,diminished IL-4 and IL-10-producing CD4+ T cells, promoted a pro-inflammatorycytokine milieu and reduced parasite load within the myocardium during theacute phase. As a direct consequence of these events, there was a reduction inserum levels of creatine kinase muscle-brain isoenzyme (CK-MB), a myocardial-specificinjury marker and an improvement in the electrocardiographic characteristicsduring the chronic phase. Our results demonstrate that purinergic system drivesthe myocardial immune response after infection and harbors a promisingpotential as a therapeutic target.