CELLULAR AND MOLECULAR MECHANISMS BEHIND NLRP3 INFLAMMASOME ACTIVATION

• Grant number: 15/21168-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 01, 2016
• End date: February 28, 2017
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Tárcio Teodoro Braga
• Supervisor: Eicke Latz
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universität Bonn, Germany
• Associated to the scholarship: 14/06992-8 - Cellular, molecular and immunological mechanisms generated through NLRP activation, BP.PD

Abstract

Inflammatory responses are initiated by activation of a range of germ-line encoded innate immune signaling receptors that respond to host-derived danger signals during tissue damage. Induction of the inflammasome NLRP3 by endogenous ligands indicates that there is a potential link between the innate immune system and the maintenance of homeostasis of the organism. In the present study we aim to evaluate the role of the NLRP3 during the course of experimental autoimmune encephalopathy (EAE) and to evaluate the immune cell responsiveness in 2000 deeply phenotyped participants from the general population and 600 patients from cohorts of Neurodegenerative Diseases patients. Recent evidences from basic science in innate immunity and preclinical disease models points to a fundamental role for the NLRP3 inflammasome as a sensor of metabolic changes and danger signals that are present in inflamed tissues. Our previous results suggest soluble uric acid, released during the EAE, is able to trigger NLRP3 activation and we have solid evidences indicating NAIP1 as an upstream sensor in such inflammasome signaling. The internship in Professor Latz's group will allow a better investigation of specific macrophage's NLRP3 and the role of NAIP1 in the context of EAE by using new technologies and specific mice strains, being the requirement of animal model already submitted to ethics committee. While the data emerging from basic science on the connection of inflammation and disease pathogenesis are compelling, an innovative translation of these scientific findings into clinical practice is largely lacking. In this sense, we will access immune responsiveness in patient populations to profile innate immune activators that can define not only the individual's threshold for immune cell activation but also the overall responsiveness and magnitude of immune activation, which conceivably could be pathogenically linked to disease susceptibility.