CÉLULAS SUPRESORAS MIELOIDES SENSIBLES A 5- FLUOROURACILO REGULA LA INFLAMACIÓN DURANTE LA INFECCIÓN AGUDA EXPERIMENTAL CON TRYPANOSOMA CRUZI.

AROCENA A; ONOFRIO L; PAROLI A; CANO R; AOKI M; GEA S

Mar del Plata, Argentina

Otro; Reunión Científica Anual de la Sociedad Argentina de Inmunología y Sociedad Argentina de Investigación Clínica; 2012

Sociedad Argentina de Inmunología

CÉLULAS SUPRESORAS MIELOIDES SENSIBLES A 5- FLUOROURACILO REGULA LA INFLAMACIÓN DURANTE LA INFECCIÓN AGUDA EXPERIMENTAL CON TRYPANOSOMA CRUZI. Arocena A, Onofrio L, Paroli A, Cano R, Aoki M, Gea S. Myeloid-derived suppressor cells (MDSC), CD11b+Gr1+, are main players of the immune suppressive network. Previously, we reported that during acute infection with the causative agent of Chagas disease, Trypanosoma cruzi, BALB/c mice showed a lesser inflammatory response and improved survival than B6 mice which developed severe inflammation and pathology. Recent studies have demonstrated the MDSC presence in this scenario though the suppressor mechanisms have not been fully explored. In this study we demonstrated a higher increase of MDSC in spleen and liver of infected BALB/c compared to B6 mice. The phenotypic analysis of two major MDSC subsets revealed a greater number of granulocytic cells (CD11b+LY6G+LY6Clow) in spleen from BALB/c respect to B6 mice whereas monocytic population (CD11b+LY6G?LY6Chigh) was the predominant subset in the liver of both mouse strains. Notably, splenic MDSC purified from infected BALB/c mice inhibited the ConA induced splenocyte proliferative response. Mechanistic studies demonstrated that inhibitors of reactive oxygen species (NAC) and nitric oxide synthase (L-NMMA) restored the proliferation. In addition, an up-regulation of NADPH oxidase p47 phox subunit and p-STAT3 occurred in MDSC. A higher number of infected CD8+ T-cells suffered surface-nitration compared to uninfected controls. Infected IL-6 deficient mice showed less recruitment of MDSC and impaired survival. Remarkably, the in vivo depletion of MDSC by 5FU led to an increased production of IL-6, IFNγ and Th17 response with increased parasitemia and mortality. In summary, our data show for the first time the mechanisms of MDSC as crucial regulators of inflammation during T. cruzi infection.