Analysis of DAMPs released in response to citosolic flagellin

• Grant number: 13/13823-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2013
• End date: June 30, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Karina Ramalho Bortoluci
• Grantee: Laura Migliari Branco
• Host Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Cell death and injury often lead to the release or exposure of intracellular molecules called damage associated molecular patterns (damps - damage-associated molecular patterns). The damps noninflammatory perform functions in living cells but acquire immunomodulatory properties when released, secreted, modified or exposed on the cell surface during stress, damage or cellular injury. In recent years, new processes of inlammatory death have been described,such as pyroptosis and lysossomal death. In those processes,the cells lose membrane integrity, resulting in the release of DAMPS. These processes are triggered by intracellular infections and, although they are regulated by different molecular machineries, both are involved in the control of these infections.The flagellin, monomeric subunit of bacterial flagellum, when present in the cell cytosol activates the inflammasome NLRC4/NAIP5, which induces activation of caspase-1, with subsequent maturation and secretion of IL-1 and IL-18 and cell death by pyroptosis. Besides pyroptosis, recent studies made by our group demonstrated that cytosolic flagellin is able to induce the activation of lysosomal pathways, which culminate in the induction of an inflammatory process of cell death, independent of inflammasome regulated by cathepsins. It is believed that the content of endogenous cellular extravasation observed in these processes is responsible for creating a microenvironment with recruitment of inflammatory effector cells able to contain the infection. However, the nature of the molecules released in these settings is not known, as is the role of these molecules in cell activation and infection control. Since knowledge of the biological role of molecules induced during infectious processes is of utmost importance for the development of new therapeutic strategies and vaccine, the goal of this project is to evaluate the influence of the processes of cell death induced cytosolic flagellin in the release of the DAMPs HMGB1, IL-1alpha, uric acid and ATP by macrophages and the role of those DAMPs in the maturation of dendritic cells (DCs).