Study of the impacts of VHL-mediated HIF-1alpha stabilization on the metabolism and polarization of macrophages

• Grant number: 19/12560-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2019
• End date: September 30, 2021
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Guilherme Ribeiro da Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases, AP.JP

Abstract

The study of the functions of immune cells, such as macrophages, and their relationship with cellular metabolism has gained ground in the academic community. One of the targetmolecules related to macrophages metabolism is the transcription factor hypoxia induciblefactor 1 alpha (HIF-1alpha). Protein levels of HIF-1alpha are controlled by the von Hippel-Lindau factor (VHL), which signals HIF-1alpha for proteasomal degradation. The activity ofHIF-1alpha in macrophages is related to a pro-inflammatory profile and a highly glycolyticmetabolism. These proinflammatory macrophages acquire an M1 activation profile (classically activated) and secrete inflammatory cytokines such as IL-12, IL-6 and TNF and IL-1beta. The present work aims to analyze how the stabilization of HIF-1alpha, which is induced by the deletion of VHL, modulates the metabolism and the polarization of macrophages. Our hypothesis is that deletion of VHL leads to accumulation of HIF-1alpha and increased pro-inflammatory response due to an increased glycolytic tone. Understanding how the regulation of HIF-1alpha in macrophages is related to the inflammatory response may contribute to novel therapeutic advances for diseases immune-mediated diseases.