Effect of beta 2 adrenergic receptor-Nur77 axis on metabolic reprogramming of macrophages

• Grant number: 21/11220-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: March 10, 2022
• End date: March 09, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandre Salgado Basso
• Grantee: Beatriz Marton Freire
• Supervisor: Carlie J.M. de Vries
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: University of Amsterdam (UvA), Netherlands
• Associated to the scholarship: 17/26242-1 - Activation of adrenergic receptors on macrophages and its influence on the development and course of Experimental Autoimmune Encephalomyelitis (EAE), BP.DD

Abstract

Macrophages are very heterogeneous immune cells that are responsible for the maintenance of tissue homeostasis. Upon tissue injury or infection, macrophages are promptly activated and start to orchestrate the innate immune response, mediated in part by the production of chemokines and cytokines to attract and activate other immune cells. Metabolic reprogramming is an essential process for macrophages to acquire a pro-inflammatory phenotype. Neuro-immune interactions occur in various types of tissues and are crucial to modulate immune responses by different mechanisms. Catecholamine produced by sympathetic nervous fibers binds to adrenergic receptors expressed by immune cells inducing different outcomes. Although there is an increase in the number of studies addressing adrenergic modulation of immune effector functions, little is known how adrenergic receptors modulate the metabolic reprogramming of macrophages. By treating murine bone marrow-derived macrophages with fenoterol, a beta 2 adrenergic receptor (B2AR) agonist, we showed that B2AR engagement diminishes total ROS, mitochondrial ROS, nitric oxide, and lactate production upon classical macrophage activation with LPS plus IFN-gamma. This effect was not associated with a change in gene expression of glycolytic enzymes, which led us to conclude that B2AR activation is not inhibiting glycolysis, but rather sustains the oxidative phosphorylation (OXPHOS). RNAseq analysis demonstrated that B2AR activation induces the expression of Nur77, a key protein in fine-tuning the pro-inflammatory response of macrophages. We hypothesize that Nur77 is mediating the effect of B2AR activation on the metabolic reprogramming of macrophages. In this project, by using Nur77-deficient murine bone marrow-derived macrophages and lentivirus transduction approaches, we propose to evaluate the B2AR-Nur77 axis in modulating metabolic reprogramming of activated macrophages. (AU)