DIFFERENT RESPONSIVENESS TO AHR LIGANDS OF MACROPHAGES FROM B6 AND BALB/C MICE: IMPACT ON T. CRUZI INFECTION

ELIZALDE, C; AMBROSIO, LF; VOLPINI, XIMENA; MOTRAN, CLAUDIA C

Mar del Plata

Congreso; LXII Reunión científica de la Sociedad Argentina de Inmunología y LIX REUNIÓN CIENTÍFICA ANUAL Sociedad Argentina de Investigación Clínica; 2014

SAI-SAIC

Despite being more resistant to T. cruzi infection than BALB/c mice, B6 mice are unable to expand Treg cells populations and show high mortality due to an imbalance between pro- and antiinflammatory mediators. AhR is a ligand-activated transcription factor that binds xenobiotics that has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems. Macrophages (Mo) and dendritic cells activation by TLR-ligands stimulate AhR expression which is necessary for IDO induction, kynurenines production and Treg and Tr1 cells expansion. AhR signaling can be activated by TCDD (xenobiotic), endogenous agonists like ITE, kynurenines and it is possible that constituents from microorganisms interact with AhR. The polymorphism in AhR system influence responsiveness to AhR ligands. B6 and BALB/c express AhRb-1 and AhRb-2 alleles respectively, and both strains were classified on the basis of TCDD induced CYP1A1 expression as high responder. Our hypothesis is that the differential innate immune response and Treg development observed between both mice strains after T. cruzi infection may be influenced by functional polymorphisms of AhR. Mo from mice of BALB/c and B6 strains were treated with TCDD (160 nM), ITE (100 nM) and T. cruzi lisate (10 ug/ml) for 24 h and the expression of Cyp1a1, ahr and ido 1 determined by qPCR. AhR and ido 1 expression was not affected by different ligands in both mouse strains. As was demonstrated, both AhR alleles showed similar Cyp1a1 induction by TCDD, while Mo AhRb-2 (Balb/c) stimulated with ITE or T. cruzi showed 2-fold increase in Cyp1a1 expression compared to Mo AhRb-1 (B6). In addition, Cyp1a1 induced by T. cruzi was inhibited by the addition of CH223191 (AhR antagonist). Moreover, TCDD and ITE induced AhR-dependent secretion of pro-inflammatory (TNF and IL-6) or IL-10 in B6 Mo and Balb/c Mo respectively. These results suggest that the less responsive AhR allele present in B6 mice may define the magnitude of the inflammatory responses and Treg induction during T. cruzi infection.