Abstract
Macrophage galactose-C type lectin (MGL)1 receptor is involved in the recognition of Trypanosoma cruzi (T. cruzi) parasites and is important for the modulation of the innate and adaptive immune responses. However, the mechanism by which MGL1 promotes resistance to T. cruzi remains unclear. Here, we show that MGL1 knockout macrophages (MGL1−/− Mφ) infected in vitro with T. cruzi 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−/− Mφ stimulated in vitro with T. cruzi antigen (TcAg) 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−/− Mφ exposed to TcAg. 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 T. cruzi infection.
Highlights
The C-type lectins are a superfamily of more than 1000 proteins that are identified by having one or more characteristic C-type lectin-like domains (CTLDs) [1,2]
After stimulation with T. cruzi antigen (TcAg) for 24 or 48 h, MGL1 expression increased significantly while MGL2 expression increased moderately (Figure 1a,b; WT-Mφ, gray shadow). These observations indicate that MGL1 receptor is highly expressed, and it is mostly induced by the TcAg in WT peritoneal exudate Mφ (PE-Mφ), compared to MGL2 expression
These results demonstrate that BMMφ from MGL1−/− mice are unable to upregulate
Summary
The C-type lectins are a superfamily of more than 1000 proteins that are identified by having one or more characteristic C-type lectin-like domains (CTLDs) [1,2]. These molecules were originally named for their ability to bind carbohydrates in a calcium (Ca+ )-dependent manner through conserved residues within the CTLDs. the CTLDs of many C-type lectins lack the components required for Ca2+ -dependent carbohydrate recognition and can recognize a broader repertoire of ligands, including proteins, lipids and inorganic molecules [3]. It has recently been shown that CLRs play an important role in promoting diverse physiological functions, such as the modulation of cellular, developmental, homeostatic and immunological responses [6,7]
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