Effect of beta2-adrenergic receptor signaling on glutamate metabolism in astrocytes: impact on Experimental Autoimmune Encephalomyelitis

• Grant number: 22/02437-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2022
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Alexandre Salgado Basso
• Grantee: Edson dos Santos Silva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Included in a large group of autoimmune diseases, Multiple Sclerosis (MS) affected about 2.8 million people globally by the year 2020, according to data from the National Multiple Sclerosis Society (2020). MS is a potentially disabling pathology because it greatly affects the Central Nervous System (CNS), and thus promotes the observed clinical symptoms. This is because the immune system mounts an unwanted inflammatory response against myelin-associated protein antigens that surround nerve fibers, failing communication between the CNS and other organs, especially skeletal muscles. Unfortunately, MS still does not have a cure, causing the medicine to resort to therapies that minimize its progression or that can treat isolated symptoms and promote a better quality of life for the patient. The experimental search in an attempt to elucidate the pathophysiological mechanisms of MS led to the development of an experimental model, Experimental Autoimmune Encephalomyelitis (EAE), which mimics aspects of the inflammation that occurs in MS. In the CNS, several cells are altered by the inflammatory microenvironment installed in MS and EAE, and one of these cells is astrocytes. These cells have several key functions in the CNS, such as energy support to neurons, maintenance of the blood-brain barrier, and clearance of toxicity exerted by concentrations of neurotransmitters, especially glutamate, which in high concentrations results in neuronal excitotoxicity and cell death. In an attempt to minimize exacerbated inflammatory events, the CNS can be regulated by anti-inflammatory pathways that are regularly activated in resident cells of the nervous system, with adrenergic receptors being one of these potential pathways, and of particular interest, ²2AR. It is known that the inflammatory environment hinders the clearance of glutamate from the negative regulation of its transporters (EAATs). Furthermore, in MS/EAE, ²2AR receptors are downregulated, which may contribute to the inflammatory environment. Given the above, in this project, we aim to explore how adrenergic signaling (²2AR) can modulate glutamate metabolism in astrocytes, which can potentially alter the development and/or course of EAE/MS. (AU)