Osteopontin-dependent regulation of Th1 and Th17 cytokine responses in Trypanosoma cruzi-infected C57BL/6 mice

Abstract

Osteopontin (OPN) is a multifunctional protein participating in the regulation of different Th cell lineages and critically involved in the initiation of immune responses to diverse pathogens. Our study goal was to verify whether OPN helps modulate the protective Th1 and Th17 cytokine responses in C57BL/6 mice infected with Trypanosoma cruzi, the etiological agent of Chagas disease. Parasite infection induced OPN release from murine macrophages in vitro and acute Chagas mice displayed enhanced serum levels of this cytokine at the peak of parasitemia. Upon administration of a neutralizing anti-OPN antibody, recently infected mice presented lower Th1 and Th17 responses, increased parasitemia and succumbed earlier and at higher rates to infection than non-immune IgG-receiving controls. The anti-OPN therapy also resulted in reduced circulating levels of IL-12 p70, IFN-c, IL-17A and specific IgG2a antibodies. Furthermore, antibody-mediated blockade of OPN activity abrogated the ex vivo production of IL-12 p70, IFN-c and IL-17A, while promoting IL-10 secretion, by spleen macrophages and CD4+ T cells from T. cruzi-infected mice. Th1 and Th17 cytokine release induced by OPN preferentially involved the avb3 integrin OPN receptor, whereas concomitant down-modulation of IL-10 production would mostly depend on OPN interaction with CD44. Our findings suggest that, in resistant C57BL/6 mice, elicitation of protective Th1 and Th17 cytokine responses to T. cruzi infection is likely to be regulated by endogenous OPN.