Neurodegeneration and macrophages; a beneficial or harmful role for macrophages and microglia in neuronal damage during multiple sclerosis

Abstract

Axonal loss and neuro-inflammation are two early hallmarks of multiple sclerosis (MS), which is a chronic neurodegenerative disease of the central nervous system (CNS). Removing myelin and neuronal debris is a general role for microglia to maintain CNS homeostasis and to promote remyelination. However, during neuro-inflammation in MS two phenotypes of activated macrophages (M1 and M2) are present in active and chronic active MS lesions. They originate from bone marrow or the yolk sac and are named bone marrow-derived macrophages or resident microglia respectively. Several studies suggest a dual role for macrophages in MS, when they are activated they might play a neurotoxic or a neuroprotective role. A phenotypic switch of macrophages induces M1 macrophages in active MS lesions, which leads to an enhanced level of pro-inflammatory cytokines. Macrophages produce neurotrophic factors to communicate with neurons, which is essential to promote neuronal survival. Some of the current therapies for MS are based upon regulation of M1 and M2 macrophages, to reduce neuronal loss. We propose that macrophages play both a harmful and beneficial role in neuroregeneration in which clearance of debris and secretion of macrophage-derived cytokines results in neuronal protection. Conversely, ROS, NO and pro-inflammatory cytokines secreted by M1 macrophages promote neuronal damage. During MS the clearance of debris and the production of cytokines that promote neuronal survival might be inhibited.