Interaction between NLRP3 and NLRC4 inflamassomes in macrophages activation

• Grant number: 15/09029-7
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): December 01, 2015
• Effective date (End): June 30, 2019
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal researcher: Karina Ramalho Bortoluci
• Grantee: Laura Migliari Branco
• Home Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 17/21814-7 - Role of NLRP3 and lysosomal cathepsins in NLRC4 inflammasome activation, BE.EP.DD

Abstract

The inflamassomes are protein complexes of high molecular weight formed after recognition of pathogens or damage signals (DAMPs) in the cellular cytosol. After activation, the inflamassomes activate caspase-1 and caspase-1, mediates the processing and secretion of the cytokines IL-1beta and IL-18 and also cell death by pyroptosis. More recently, new effector functions have been assigned to inflamassomes, such as activation of enzymes involved in microbicide capacity of macrophages, the release of DAMPs and lipid mediators and activation of the adaptive immune response. Among the inflamassomes, the best characterized are NLRP3 and NAIP/NLRC4. The NLRP3 inflammasome is activated by a variety of stimuli such as viral pathogens, fungi, protozoa and bacteria, DAMPs and forming pore toxins, as nigericin. The NAIP/NLRC4 inflammasome recognizes the secretion system and the flagellin protein of virulent bacteria that reach the cytoplasm. Recent data suggests that different inflamassomas interact, working together to mount appropriate responses against pathogens. Preliminary results obtained by our group are in accordance with the literature, since it suggests that in peritoneal macrophages, NLRC4 and NLRP3 receptors interact functionally in response to flagellin and nigericin. Nevertheless, it still remains unclear how these proteins interact, and the relevance of this interaction for activation of effector mechanisms mediated by inflamassomes. Understanding the molecular mechanisms responsible for the formation and regulation of the inflamassomes activity is of utmost importance to identify potential targets for the treatment of infectious diseases and inflammatory diseases related to malfunction of these molecular machinery. In this work, we intend to elucidate how occurs the interaction between NLRC4 and NLRP3 in response to cytosolic flagellin and nigericin. (AU)