Inflammation in neurodegenerative diseases

Abstract

Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Apart from the pathogenic role of immune responses, emerging evidence indicates that immune responses are also critical for neuroregeneration. Here, we review the impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and discuss their contribution to either damage or repair. We also discuss potential therapies aimed at the immune responses within the central nervous system. A better understanding of the interaction between the immune and nervous systems will be crucial to either target pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic neurodegenerative diseases.

Figure 1

Pathology of human and experimental neurodegenerative disorders showing involvement of the immune response. (a) Toll-like receptor 3 (TLR3) expression in neurons in multiple sclerosis (MS). The insert shows the granular appearance of the receptor in the cytoplasm (arrow). (b) Activated microglia, as depicted by human leucocyte antigen (HLA) class II expression (blue) around amyloid-beta (Aβ)-positive accumulations (red) inside neurons in Alzheimer’s disease. (c) HLA class II expression by activated microglia (blue) phagocytosing myelin basic protein (red) in stroke. (d) Lipid-laden (oil red O positive) foamy macrophages (blue) in an active MS lesion. (e) HLA class II-positive microglia (brown) at the edge of a chronic active lesion in MS. Activated microglia/macrophages surrounding a blood vessel in the lesion (arrow). (f) CD45⁺ lymphocytes (arrow) and (g) CD20⁺ B cells (brown) in perivascular infiltrates in MS. (h) HLA class II-positive microglia (blue) close to a damage axon red (arrow) stained for neurofilament light (NF-L). (i) Meningeal infiltrate in acute bacterial meningitis containing a single CD20⁺ cell (brown). The majority of cells are polymorphonuclear cells (inset). (j, k) Shrunken and swollen axons (arrows) in the spinal cord of mice with experimentally induced neuronal damage following immunization with NF-L. In the same mice, CD3⁺ T cells (l), and (m) B cells in the meninges close to areas of neuronal degeneration, are shown.

Figure 2

Proposed mechanisms of viral-induced neuronal damage and the outcomes. 1. Infection of neurons with viruses leads to apoptosis, necrosis or autophagy (A). 2. Immune-mediated attack of neurons by viral-specific immunity by, for example, CD8⁺ T cells, leads to direct cytotoxic death, apoptosis, autophagy (A), dying back of the neurons (B) or neuronal death (C) and myelin damage. 3. Infection of cells (e.g. astrocytes) leads to so-called bystander damage as the result of release of cytokines or reactive oxygen species (ROS) that damage neurons in a variety of ways (A–C).

Figure 3

Pathways of immune-mediated neurodegeneration. In the inside-out model, immune-mediated damage leads to direct neuronal damage or axonal loss. As a result, myelin degenerates. In the outside-in model, as a result of direct attack on myelin, axons are vulnerable to damage by, for example, reactive oxygen species (ROS), leading to neuronal damage and degeneration.

Figure 4

Proposed mechanisms of immune involvement in neurodegeneration and neuronal repair. Damage to neurons or mutations in proteins leads to misfolded or aggregated proteins (i) while macrophage and microglia activation stimulates, for example, reactive oxygen species (ROS) production known to induce mitochondrial dysfunction that could, unchecked, lead to neuronal damage, (ii) CD8 T-cell-mediated cytotoxicity, (iii) induced Fas:FasL or perform mediated damage, and (iv) excess glutamate leading to exocitotoxicity. Neuroprotection and regeneration is afforded by cells of the immune system. T cells secrete neuroprotective factors and suppress pro-inflammatory responses, while macrophages/microglia carry out phagocytosis and astrocytes stimulate growth and repair via glial cell-derived neuronal growth factors. Endocannabinoids inhibit glutamate cytotoxicity. IL, interleukin; MMPs, matrix metalloproteinases; NO, nitric oxide; Th2, T helper 2; T reg, T regulatory.