Macrophage migration inhibitory factor (MIF) has been found to be involved in host resistance to several parasitic infections. To determine the mechanisms of the MIF-dependent responses to Trypanosoma cruzi, we investigated host resistance in MIF-/- mice (on the BALB/c background) during an intraperitoneal infection. We focused on the potential involvement of MIF in dendritic cell (DC) maturation and cytokine production. Following a challenge with 5 x 103 T. cruzi parasites, wild type (WT) mice developed a strong IL-12 response and adequate maturation of the draining mesenteric lymph node DCs and were resistant to infection. In contrast, similarly infected MIF-/- mice mounted a weak IL-12 response, displayed immature DCs in the early phases of infection and rapidly succumbed to T. cruzi infection. The lack of maturation and IL-12 production by the DCs in response to total T. cruzi antigen (TcAg) was confirmed by in vitro studies. These effects were reversed following treatment with recombinant MIF. Interestingly, TcAg-stimulated bone marrow-derived DCs from both WT and MIF-/- mice had increased ERK1/2 MAPK phosphorylation. In contrast, p38 phosphorylation was only upregulated in WT DCs. Reconstitution of MIF to MIF-/- DCs upregulated p38 phosphorylation. The MIF-p38 pathway affected MHC-II and CD86 expression as well as IL-12 production. These findings demonstrate that the MIF-induced early DC maturation and IL-12 production mediates resistance to T. cruzi infection, probably by activating the p38 pathway.

Macrophage migration inhibitory factor (MIF) has been found to be involved in host resistance to several parasitic infections. To determine the mechanisms of MIF-dependent responses to Trypanosoma cruzi (Queretaro strain), we investigated host resistance in MIF-/- mice (BALB/c background) during an intraperitoneal (i.p.) infection. We focused on the potential involvement of MIF on Dendritic Cell (DC) maturation and cytokine production. Following i.p. T. cruzi infection, wild type (WT) mice developed a strong IL-12 response with an adequate maturation of their DC in draining mesenteric lymph node (MLNDC), these mice were resistant to a challenge with 5x103 parasites. In contrast, similarly infected MIF-/- mice mounted a weak IL-12 response, displayed immature MLNDCs in the early phases of infection and rapidly succumbed to a similar challenge. Lack of maturation and IL-12 production of DCs in response to total or soluble T. cruzi antigens was confirmed by in vitro studies, such effects were reversed following treatment with recombinant MIF. Interestingly, whereas DC from WT mice exposed to total T. cruzi antigens had ERK1/2 MAPK phosphorylation, MIF-/- DC did not. These findings demonstrate that MIF-induced early DC maturation and IL-12 production mediate resistance to T. cruzi infection, probably by activation of ERK1/2 MAPK pathway.

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The C-type lectin receptor mMGL is expressed exclusively by myeloid APC such dendritic cells and macrophages (MΦ), mediates binding to glycoproteins carrying terminal N-acetylgalactosamine (GalNAc) residues. Parasite glycosylated molecules are recognized by mMGL. T. cruzi parasite expresses large amounts of mucins (TcMUC)-like glycoproteins, here we show by Jacalin lectin-blot that GalNAc moieties are also expressed on their surface. Then, our goal was to study the impact of mMGL in T. cruzi infection. Male mMGL knockout (KO) and wild-type (WT) C57BL/6 mice were infected via intraperitoneal (i.p.) with 10-5 trypomastigotes of T. cruzi (Queretaro strain). Following i.p. T. cruzi infection, mMGL-KO mice developed higher parasitemia load and higher mortality associated with poor production of Nitric Oxide (NO), IL-12 and TNF-α by MΦ in response to total soluble T. cruzi antigens compared to WT. Interestingly, whereas heart from WT mice infected with T. cruzi did not present amastigotes nest, mMGL-KO mice did. We conclude that mMGL have an important role during the invasion of T. cruzi to the host cell, also induce inflammatory cytokines and NO production by macrophages.