PCK2 repression drives early fumarate accumulation in LPS-activated macrophages

• Grant number: 24/14812-1
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: January 25, 2025
• End date: July 24, 2025
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Paulo Estevão Ferreira Macêdo
• Supervisor: Luke Anthony John O'Neill
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Trinity College Dublin, Ireland
• Associated to the scholarship: 23/05714-3 - Study of the role of gluconeogenesis in inflammatory macrophages, BP.MS

Abstract

Macrophages play a central role in the pathophysiology of multiple diseases. Their plasticity allows them to adopt inflammatory or resolutive profiles depending on the microenvironment and relies on reprogramming of cellular metabolism. Recently, TCA cycle-derived metabolites, such as succinate, ¿-ketoglutarate, itaconate and fumarate, have emerged as key mediators of macrophages resolutive or inflammatory effector functions. Fumarate is an oncometabolite that accumulates under LPS stimulus and modulates macrophages response through multiple pathways. However, the mechanisms that underlie early fumarate accumulation are incompletely understood. Our data shows that HIF-1¿ represses PCK2 (phosphoenolpyruvate carboxykinase 2) in LPS-activated macrophages. PCK2 is the mitochondrial gluconeogenesis rate-limiting enzyme, and its repression is described to increase the levels of intracellular fumarate in tumor cells. It is possible that this effect also takes place in macrophages. This is important because fumarate was recently described as an electron acceptor and a strong immune regulator, which could directly affect macrophage redox state and immune response. Therefore, we hypothesize that HIF-1¿-dependent PCK2 repression drives early fumarate accumulation in LPS-activated macrophages, which may affect the overall response and redox state of the cell. If confirmed, this undescribed mechanism will add a new layer of understanding to how macrophages metabolic reprogramming supports its response to inflammatory stimuli.