Study of the role of gluconeogenesis in inflammatory macrophages

• Grant number: 23/05714-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Paulo Estevão Ferreira Macêdo
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease, AP.TEM
• Associated scholarship(s): 24/14812-1 - PCK2 repression drives early fumarate accumulation in LPS-activated macrophages, BE.EP.MS

Abstract

Macrophages are antigen presenting phagocytes that play a central role in the pathophisiology of many diseases. Their plasticity allows them to adopt pro (M1-like) or anti-inflammatory (M2-like) profiles depending on the surrounding cytokine and substrate microenvironment. This versatily relies on their capability to reprogramm cellular metabolism in order to supply its basal energetic demands and execute immune functions. M1-like cells center their metabolism on glycolysis, while those M2-like adopt the oxidative phosphorylation (OXPHOS) as the main metabolic route. Most studies investigate macrophage immunometabolism in media with high glucose concentration. Therefore, this metabolic dichotomy (glycolysis vs OXPHOS) observed for M1-like and M2-like macrophages, respectively, reflects, in reality, results from a simple model that ignores the probable metabolic reprogramming and activation profiles adopted under distinct extracellular substrate concentrations. Although it is known that macrophages cultured under elevated glucose concentrations secrete high levels of pro-inflammatory cytokines, the response of these cells under glucose shortage or deprivation - as well as the metabolic pathways that sustain this response - remain largely unexplored. This question needs to be addressed, since this cellular population survive and exert effector functions in low glucose environments, such as tumors and chronic inflamed tissues. Recent findings show that myeloid and lymphoid cells populations not only perform gluconeogenesis, but rely on it to survive and exert their functions. We hypothesize that macrophages function and survival under glucose shortage dependes on gluconeogenesis. By adopting in vitro and in vivo models of gene silencing for gluconeogenic enzymes, in different substrate concentrations, we expect to find quantitative differences in the activation markers of these cells. This finding would reveal an undescribed mechanism of macrophage response modulation, putting gluconeogenesis as a potential target for the development of strategies that regulate the host immune response in pathological conditions in which macrophages play a relevant role.