CNS inflammation and neurodegeneration
Tanuja Chitnis, Howard L. Weiner
Tanuja Chitnis, Howard L. Weiner
Published October 2, 2017; First published September 5, 2017
Citation Information: J Clin Invest. 2017;127(10):3577-3587. https://doi.org/10.1172/JCI90609.
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Category: Review Series

CNS inflammation and neurodegeneration

Abstract

There is an increasing recognition that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and the prototypic neuroinflammatory disease multiple sclerosis (MS). Differential immune responses involving the adaptive versus the innate immune system are observed at various stages of neurodegenerative diseases, and may not only drive disease processes but could serve as therapeutic targets. Ongoing investigations into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms by which inflammation, mediated either by the peripheral immune response or by endogenous CNS immune mechanisms, can affect CNS neurodegeneration.

Authors

Tanuja Chitnis, Howard L. Weiner

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Figure 1

Immune-mediated attack on axons and myelin sheath.

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Immune-mediated attack on axons and myelin sheath. During MS and EAE, ax...
During MS and EAE, axonal damage and demyelination are initially mediated by the inflammatory response within the CNS. (i) CD4+ Th17 cells produce GM-CSF, which activates macrophages and microglia. (ii) CD4+ Th1 cells invade the CNS and produce IFN-γ, which activates macrophages and microglia to produce the cytokine IL-12 (the major promoter of Th1 cytokine production). (iii) Macrophages and microglia also produce nitric oxide (NO), peroxynitrite (ONOO–), and superoxide (O2–), which are each capable of mediating cellular damage. This capability is enhanced by microglia- and macrophage-derived TNF-α production. (iv) Activated macrophages and microglia may also consume damaged myelin sheaths and axons. (v) B cells produce antibodies that bind to myelin sheaths and may promote complement-mediated damage (C′). (vi) IFN-γ upregulates the expression of MHC class I by resident CNS cells, potentially inciting a CD8+ cytotoxic T cell response.