Disruption of interactions between immunocytes, glia and neurons in demyelinating diseases: A view from neuroscience

Abstract

Microglia play a crucial role in the development of inflammatory demyelinating lesions in multiple sclerosis (MS). Microglia act on inflammatory lymphocytes as antigen presenting cells, and produce inflammatory cytokines, glutamate, and reactive oxygen species (ROS). Neuro degeneration, which is observed in the demyelinating lesions, affects the prognosis in MS. Neuritic beading, focal bead-like swellings of the dendrites and axons, is a neuropathological sign in the early phase of neuro degeneration in MS. Microglia-derived glutamate and ROS initiate beading formation. Microglia can exert neuroprotective effect by deprivation of dead cells and induction of neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant enzyme in MS. Neurons are thought to be not merely passive targets of microglia but rather control microglial activity through various signals including cytokines and chemokines. Soluble fractalkine (sFKN), which is secreted from damaged neurons by glutamate, promotes microglial phagocytosis of neuronal debris, and induces the antioxidant enzyme heme oxygenase-1 in microglia. IL-34 secreted from neurons also induces microglial neuroprotection. Astrocytes exert neuroprotective effect. However, toll-like receptor ligands induce neurotoxic molecules in astrocytes. IL-33 produced by astrocytes induces microglial activation. Thus, disruption of beneficial interaction between glia and neurons is crucial for the pathogenesis of MS.