IL-6 regulates insulin resistance and cardiovascular disease during Trypanosoma cruzi experimental infection

PONCE, NE; CANO, RC; SANMARCO, LM; BERGERO, GASTÓN; AOKI, MP; EBERHARDT, N; VIGLIANO, C

Congreso; Reunión conjunta de Sociedades de Biociencias; 2017

Oxidative stress generation is proposed as the common pathogenic factor mediating the appearance of insulin resistance while producing increased cardiovascular risk. We have recently reported a potent anti-oxidant effect of IL-6, so we hypothesize that IL-6 could be involved in insulin sensitivity and cardiovascular function during T. cruziinfection. We observed that infection induces increased frequency of nitric oxide (NO)-producing monocytes in peripheral blood from  IL-6-deficient  mice  (KO)  in  comparison  with  C57BL/6  (WT) mice at all days post-infection (dpi) studied (0 dpi p=0.0301, 4 dpi p=0.0006, 14 dpi p=0.0007, 21 dpi p=0.0165). Among the metabolic parameters assayed in plasma, we observed increased glucose (p=0.0120) and insulin (p=0.0286) levels, with the consequent augmented HOMA-IR index (p=0.0197) at 14 dpi in KO mice compared to  WT  mice.  These  results  suggest  that  IL-6-deficiency  induces acute insulin resistance. The fatty acid transporter and scavenger receptor  CD36  is  implicated  in  the  pathogenesis  of  insulin  resistance and associated cardiovascular complications. Considering that KO mice showed higher frequency of CD36+ circulating monocytes (p=0.0045) in comparison with WT mice at 14 dpi, we analyzed if IL-6 could be regulating insulin sensitivity by modulating this scavenger receptor. IL-6 stimulation of T. cruzi-infected bone marrow-derived macrophages (BMDM) diminished the frequency of CD36+ BMDM and increased the percentage of insulin receptor+ BMDM compared to unstimulated-infected cells. Considering that cardiovascular dysfunction is a complication of metabolic syndrome, we observed that KO mice showed increased creatin-kinase (CK) MB/total CK ratio (p=0.0016) and creatinine plasmatic levels (p=0.0003), biomarkers of cardiac and kidney damage respectively, in comparison with WT mice. Altogether,  the  data  obtained  show  that  IL-6  protects  mice from T. cruzi-induced oxidative stress and the consequent insulin resistance and kidney dysfunction