| Summary: | Macrophage galactose-C type lectin (MGL)1 receptor is involved in the recognition of <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>) parasites and is important for the modulation of the innate and adaptive immune responses. However, the mechanism by which MGL1 promotes resistance to <i>T. cruzi</i> remains unclear. Here, we show that MGL1 knockout macrophages (MGL1<sup>−/−</sup> Mφ) infected in vitro with <i>T. cruzi</i> were heavily parasitized and showed decreased levels of reactive oxygen species (ROS), nitric oxide (NO), IL-12 and TNF-α compared to wild-type macrophages (WT Mφ). MGL1<sup>−/−</sup> Mφ stimulated in vitro with <i>T. cruzi</i> antigen (<i>Tc</i>Ag) showed low expression of TLR-2, TLR-4 and MHC-II, which resulted in deficient splenic cell activation compared with similar co-cultured WT Mφ. Importantly, the activation of p-ERK1/2, p-c-Jun and p-NF-κB p65 were significantly reduced in MGL1<sup>−/−</sup> Mφ exposed to <i>Tc</i>Ag. Similarly, procaspase 1, caspase 1 and NLRP3 inflammasome also displayed a reduced expression that was associated with low IL-β production. Our data reveal a previously unappreciated role for MGL1 in Mφ activation through the modulation of ERK1/2, c-Jun, NF-κB and NLRP3 signaling pathways, and to the development of protective innate immunity against experimental <i>T. cruzi</i> infection.
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