HIF-1ALFA/purinergic axis is altered in patients with chronic Chagas disease

EBERHARDT, N; VISCONTI, LM; AOKI, MP; BERGERO, GASTÓN; VIGLIANO, C; SANMARCO, LM; MINGUEZ, RA

Exposición; REUNION ANUAL DE A SOCIEDAD ARGENTINA DE INMUNOLOGIA; 2018

The molecular mechanisms involved in the development ofhuman chronic Chagas cardiomyopathy (CCC) are still largely unknown. Purinergicsystem components have taken a robust significance as danger signals andmodulators of immunity. Ischemic cells release ATP (inflammasome activator),which is metabolized by CD73/CD39 ectoenzymes to the anti-inflammatoryadenosine. We have reported that CD73 pharmacological inhibition during acute T. cruzi murine infection reducedprogression of CCC. The aim of this study was to explore the hypoxia-induciblefactor-1α (HIF-1α)/purinergic system axis in immune cells from infected individualsand in cardiac explants from CCC patients analyzing the correlation with myocarditisdegree.  Seropositive patients (n = 24) were evaluatedclinically and by electrocardiogram and chest X-ray. The uninfected controlgroup (n = 24) consisted of age-matched individuals. Cardiac tissuesamples from end-stage CCC patients were stained by IHC/IF. The myocarditisdegree was determined considering the number of CD68+ plus CD3+ cells, asfollow: Severe≥median number; Moderate 25 - 50th percentile; or Mild≤25thpercentile. In comparison with control donors, infected patientsshowed higher frequency of HIF-1α+ and IL-1β+ circulating monocytes withincreased nitric oxide production (p<0.05). Moreover, while lymphocytes exhibiteddecreased expression of HIF-1α-target molecules, CD39 and CD73 (p<0.05),concomitant with augmented ATP plasma levels (p<0.05); the percentage ofCD39+ monocytes was higher. Heart samples with severe myocarditis showed aprevalence of CD3+ cells over other infiltrating mononuclear cells (p<0.001)and the number of T cells positively correlated with HIF-1α expression(p<0.05). In addition, severe CCC hearts showed higher HIF-1α expressioncompared to moderate or mild disease (p<0.05). Furthermore, a marked CD73 expressionwas observed in infiltrating and endothelial cells. Summing up, infected patients exhibited an inflammatorystate potentiated by altered purinergic pathways that may be involved incardiac dysfunction. These findings suggest that targeting the hypoxic/adenosineaxis could be used therapeutically for infected patients.