Action of Liver-X receptor (LXR) agonists on the depletion of myeloid derived supressor cells (MDSCs) in murine pulmonary paracoccidioidomycosis

Abstract

A previous study on Paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that the host immunity is strongly regulated by several suppressor mechanisms mediated by plasmocytoid dendritic cells, by the enzyme 2,3 indoleamine dioxygenase (IDO1) and regulatory T cells (Treg). The activity of IDO1 was demonstrated by orchestrating local and systemic immunosuppressive effects by the recruitment and activation of myeloid derived suppressor cells (MDSCs), a heterogeneous population of cells with strong ability to suppress T-cell responses. The MDSC regulates immune responses and tissue repair in healthy individuals and rapidly expand during a microbial infection. However, the involvement of MDSCs in PCM remains unexplored, mainly due to the scarce experimental tools that are able to depleting this cell population specifically. Recent studies have shown that the activation of Liver-X receptors, with the use of agonists in experimental models of cancer and tuberculosis, resulted in decreased frequency of MDSCs and increased amount of T cells, which led to an improvement of immune response in both cases. The specific decrease of MDSCs promoted by the activation of Liver-X receptors in cancer patients and in experimental models with Mycobacterium turberculosis, led us to propose this study to verify the ability of the agonists of Liver-X receptors to modulate the MDSCs in C57BL/6 mice infected with the fungus Paracoccidiodies brasiliensis. The presence of MDSCs will be evaluated in several post-infection periods and treatment with agonists. In addition, CFU, histology and survival will also be evaluated.