Translational regulation during macrophage activation

• Grant number: 24/01788-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: May 20, 2024
• End date: May 19, 2025
• Field of knowledge: Biological Sciences - Immunology - Immunochemistry
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Rodrigo Dias Requião
• Supervisor: Peter J Murray
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Max Planck Institute Of Biochemistry, Germany
• Associated to the scholarship: 20/15399-0 - Study of the role of mitochondria dynamics in obesity-induced inflammation, BP.PD

Abstract

Macrophages are key cells for the maintenance of tissue homeostasis, for example, through phagocytosis of dead cells, which is an immunological "silent" process. By contrast, macrophages activated by pathogens are a primary host defense mechanism and via the production of oxygen and nitrogen radicals necessary to kill pathogens, can also damage tissues. ROS production causes oxidative damage to different macromolecules within the cell, including nucleic acids, both DNA and RNA. mRNA oxidation impairs translation, which can lead to ribosomal stalling and ribosomal collisions, which activates several pathways that signal translational stress. Because pro-inflammatory macrophages produce ROS, and ROS can damage mRNA and ribosomes, a key question is how the cells maintain translation of vital host defense proteins during the inflammatory response. We hypothesize that inflammatory macrophages are under translational stress due to persistent ribosome collisions but activate a variety of translational quality control pathways to maintain protein synthesis. The identity and hierarchy of the macrophage translation quality control pathways has not been investigated in depth. We therefore propose to identify the translation dynamics of activated macrophages and the molecular mechanisms that control translation during high ROS output. The outcomes of this is proposal will allow us to identify molecular mechanisms regulating translational dynamics in both pro- and anti-inflammatory macrophages and could contribute as a new therapeutic target to modulate their activity.