Phenotypic modulation of infiltrating macrophages in the myocardium during experimental infection with Trypanosoma cruzi.

PONCE N.E.; SANMARCO L.M.; AOKI M.P.

Mar del Plata

Congreso; LXII Reunión Científica de la Sociedad Argentina Inmunología; 2014

Sociedad Argentina Inmunología

Emerging evidence points to the involvement of specialized immune cells as key drivers in the pathophysiology of cardiovascular diseases. Infection with Trypanosoma cruzi is a major cause of morbidity and mortality in Latinamerica. Innate and adaptive immune response allow for control of parasite levels, but are insufficient to completely clear the infection and most individuals remain infected for life, with parasites persisting primarily in muscle cells. Macrophages (Ma) are one of the main infiltrating leukocytes arriving to injured myocardium and they present two subpopulation: M1 (inflammatory/antimicrobial) and M2 (immunoregulatory/healing). The aim of this study was to manipulate the phenotype of Ma in murine cardiac tissue during the acute phase of the infection. We found that at early days post-infection (4dpi) M1 Ma (F4/80+CD68+CD86+CD206-) predominated over M2 (F4/80+CD68-CD86-CD206+) in Balb/c mice myocardium, but from 7dpi, Ma are sustained biased toward M2 phenotype during the acute infection (p<0.001). Moreover, tissue-resident Ma (F480hi CD11b+) exhibited a M2 phenotype throughout the infection, while infiltrating Ma (F480lo CD11b+) switched from M1 to M2 following the observed kinetic for total Ma. According to the soluble cues that lead the M1 or M2 polarization, we found in myocardium increased levels of IL17, IL12 and TNFa exclusively at 4dpi while MCP1, TGFb, IL6 and IL10 gradually augmented during the course of the infection. In order to lengthen the M1 antimicrobial Ma in the myocardium, infected mice were treated with an inhibitor of adenosine production, a purine nucleoside with immunosuppressor functions. In fact, treated mice prevented the M1 to M2 phenotypic change at 7dpi, sustaining the M1 biased profile. Together these results highlight the importance of studying new strategies to shape Ma functions in order to minimize the tissue damage, favor a properly wound-healing and eradicate the parasite.