The temporal and causal relationship between inflammation and neurodegeneration in multiple sclerosis

It is currently incompletely understood whether inflammation and neurodegeneration are causally related in multiple sclerosis (MS). The sequence of a potential causal relationship is also unknown. Inflammation is present in rather all clinical stages of MS. Its role in the pathogenesis of MS is supported by histopathological analyses, genetic data, and numerous animal models of MS. All approved disease-modifying therapies that reduce clinical relapses and diminish the accumulation of lesions on neuroimaging are anti-inflammatory. Axonal loss and accelerated brain volume loss can also be detected from clinical disease onset throughout all stages. The expression of neurofilament light chain in cerebrospinal fluid and serum, a scaffolding protein in axons and dendrites, is a biomarker of neuronal injury associated with clinical relapses and reflects neuronal loss during episodes of acute inflammation. The recent association of human endogenous retrovirus (HERV) and its envelope proteins with MS illustrates a pathogenic pathway that causally links central nervous system (CNS)–intrinsic proinflammatory effects and inhibition of myelin repair and neuroregeneration. A review of current data on the causal relationship between inflammation and neurodegeneration in MS identified numerous plausible pathomechanisms that link the two events. Observations from most experimental models appear to favor a pathogenesis in which inflammation precedes neurodegeneration.