Cytokines and Myelination in the Central Nervous System

Abstract

Myelin abnormalities that reflect damage to developing and mature brains are often found in neurological diseases with evidence of inflammatory infiltration and microglial activation. Many cytokines are virtually undetectable in the uninflamed central nervous system (CNS), so that their rapid induction and sustained elevation in immune and glial cells contributes to dysregulation of the inflammatory response and neural cell homeostasis. This results in aberrant neural cell development, cytotoxicity, and loss of the primary myelin-producing cells of the CNS, the oligodendrocytes. This article provides an overview of cytokine and chemokine activity in the CNS with relevance to clinical conditions of neonatal and adult demyelinating disease, brain trauma, and mental disorders with observed white matter defects. Experimental models that mimic human disease have been developed in order to study pathogenic and therapeutic mechanisms, but have shown mixed success in clinical application. However, genetically altered animals, and models of CNS inflammation and demyelination, have offered great insight into the complexities of neuroimmune interactions that impact oligodendrocyte function. The intracellular signaling pathways of selected cytokines have also been highlighted to illustrate current knowledge of receptor-mediated events. By learning to interpret the actions of cytokines and by improving methods to target appropriate predictors of disease risk selectively, a more comprehensive understanding of altered immunoregulation will aid in the development of advanced treatment options for patients with inflammatory white matter disorders.

Interleukin-1β Transfer across the Blood–Brain Barrier in the Ovine Fetus

“…[3][4][5][6] Cerebral ischemia initiates an inflammatory cascade in the brain that is associated with increases in pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6). 7 Increases in systemic, vascular, and endogenous parenchymal proinflammatory cytokines could exacerbate perinatal brain damage. 3 Interleukin-1β is one of the key pro-inflammatory cytokines that contributes to acute hypoxic-ischemic injury in the developing brain.…”

Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity

“…TNF-α is highly upregulated in active MS lesions [86] and was shown to be expressed by MoMF or microglia, as well as astrocytes [87]. Numerous studies found TNF-α to be detrimental in EAE, although it was also reported to be associated with decreased clinical symptoms [88]. Moreover, TNF-α was associated with anxiety behavior in MOG-immunized mice [89].…”

General Control Nonderepressible 2 (GCN2) Kinase Protects Oligodendrocytes and White Matter during Branched-chain Amino Acid Deficiency in Mice

“…Oligodendrocyte precursors are more susceptible to oxidative stress than other glial cell types (35). Cytokines produced by glial cells also significantly impact oligodendrocyte function and are linked to inflammatory white matter disorders (36). To begin to elucidate the mechanisms underlying the premature death of oligodendrocytes, we measured mRNA expression of key genes involved in antioxidant defense and inflammatory stress.…”