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.

Figure 1. Immune-mediated attack on axons and myelin sheath.

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.

Figure 2. Secondary degeneration of the axon and neuronal cell body.

Secondary degeneration may be mediated through several mechanisms. (i) Nitric oxide (NO) produced by macrophages and microglia may inhibit normal cellular respiration and mitochondrial ATP production. (ii) Reductions in neuronal ATP production may lead to failure of the Na⁺/K⁺ pump. The subsequent increases in intracellular concentrations of Na⁺ lead to reverse operation of the Na⁺/Ca²⁺ exchanger and opening of voltage-sensitive Ca²⁺ channels, resulting in a rise of intra-axonal Ca²⁺. (iii) This, in turn, may activate degradative enzymes, including proteases, phospholipases, and calpains, resulting in further neuronal or axonal damage and impaired ATP production. (iv) Microglia and macrophages recruited to the area produce glutamate, which can interact with NMDA or AMPA receptors, which also cause a rise in intracellular Ca²⁺. (v) Impaired glutamate uptake and degradation in the astrocyte, accompanied by downregulated expression of glutamine synthase (GS) and glutamate dehydrogenase (GDH), perpetuates increased extracellular glutamate levels. (vi) Astrocytes produce CCL2 and cytokines that further activate microglia and macrophages. In turn, microglia and macrophages consume damaged myelin sheaths and axons. (vii) Secondary neuronal cell body degradation can occur by apoptotic or necroptotic mechanisms, triggered in part by immune molecules (e.g., TNF-α, TRAIL) that are produced by microglia/macrophages or astrocytes.

Figure 3. Schema of antiinflammatory, proinflammatory, and phagocytosis-regulating molecules involved in the regulation of CNS monocytes.