Role of Dectin-1 and Syk kinase evaluation in Nlrp3 inflammasome activation in murine macrophages infected with L. amazonensis

Abstract

Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people and threatens over 350 million people worldwide. The parasites replicate intracellularly in macrophages and impair/bypass several signaling pathways in these cells, including those involved in the activation of innate immunity. The main mechanisms underlying host resistance involve the production of nitric oxide and reactive oxygen species, which is a transcriptionally regulated process that is not completely understood in Leishmania-infected macrophages. Studies have demonstrated that activation of innate immunity receptors in cells such as macrophages is crucial for the initiation of immune response. Initiation is achieved when host cell receptors sense microbial com¬ponents or damage signals. Members of the Nod-like receptor family of proteins, including Nlrp3, have emerged as important innate immune sen¬sors of microbes and cellular damage. Nlrp3 regulate the assembly of the inflammasome, a molecular platform that contains active caspase-1. Studies have been demonstrated that Nlrp3 can be activate by different stimulus such as reactive oxygen species generation, efflux of k+, lysosomal damage or after sensing intracellular pathogens. However, little is known about the upstream mechanisms that regulate the Nlrp3 inflammasome activation. Recently, our group showed that the NLRP3 inflammasome is a major innate immune platform for the restriction of Leishmania infection both in vitro and in vivo. The activation of the NLRP3 inflammasome was critical for the control of parasite replication in cultured macrophages and in vivo, being it is mediated by IL-1² and nitric oxide production. Thus, it becomes essential to understand the mechanisms involved in the Nlrp3 inflammasome activation in response to L. amazonensis infection. It is reported that C-type lectin receptors such as Dectin-1 participate in the Nlrp3 inflammasome activation in response to fungal infections by mechanisms dependent on the production of superoxide and Syk kinase signaling pathway. So, it is possible that the Dectin-1/Syk signaling may participate in the Nlrp3 inflammasome activation in response to Leishmania infection. In this work, we will evaluate the role of signaling pathway Dectin-1/Syk in the Nlrp3 inflammasome activation in macrophages during L. amazonensis infection. The results obtained in this study collaborate not only to elucidate the mechanisms that control the inflammasome activation, but also to understand the basic phenomena related to the initiation and control of immune response induced by this parasite that can be directly associated with the pathogenesis of leishmaniasis. (AU)