Investigation of the role of glucose concentration and hypoxia condition on inflammasome activation on macrophages

• Grant number: 24/22157-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Jonas Albuquerque Nascimento
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 19/11342-6 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens, AP.TEM

Abstract

Inflammasomes are multimeric, proteic complexes formed by intracellular receptors of NLF family, adaptor protein ASC and Caspase-1. Upon activation, it leads to cleavage and functional activation of interleukins IL-1¿, IL-18 and pore forming protein gasdermin D (GSDMD), causing inflammatory cell death, named pyroptosis. Inflammasomes require two signals for activation: the first signal, or priming, is characterized by expression of inflammasome components (such as Nlrp3 and Casp1) and its substrates (like pro-Il1b), and is mediated by NF-¿B pathway. The second signal, commonly mediated by DAMP's like Oxygen Reactive Species (ROS) and potassium efflux, leads to inflammasome oligomerization and execution of its effector functions. The most studied inflammasome is NLRP3, and recent works have shown the importance of glycolysis in modulating inflammasome activation by regulation of second signals. Transcription factor HIF (Hypoxia-Inducible Factor)-1¿ is typically stabilized in hypoxic conditions, and participates in metabolic reprogramming by inducing expression of glycolysis pathway genes, although the roles of hypoxia and HIF-1¿ on inflammasome activation remain controversial. Thus, this work aims on expanding the current knowledge on immunometabolic regulation of inflammasome activation, contributing to better understanding of diseases with hypoxic inflammation foci.