Neuroinflammation

Microglia are recognized as the innate immune cells of the central nervous system.[2] Microglia actively survey their environment through, and change their cell morphology significantly in response to neural injury.[7] Acute inflammation in the brain is typically characterized by rapid activation of microglia.[5] During this period, there is no peripheral immune response. Over time, however, chronic inflammation causes the degradation of tissue and of the blood–brain barrier. During this time, microglia generate reactive oxygen species and release signals to recruit peripheral immune cells for an inflammatory response.[7]

Astrocytes are glial cells that are the most abundant cells in the brain. They are involved in maintenance and support of neurons and compose a significant component of the blood–brain barrier. After insult to the brain, such as traumatic brain injury, astrocytes may become activated in response to signals released by injured neurons or activated microglia.[6][1] Once activated, astrocytes may release various growth factors and undergo morphological changes. For example, after injury astrocytes form the glial scar composed of a proteoglycan matrix that hinders axonal regeneration.[6] However more recent studies revealed that glia scar is not detrimental but beneficial for axonal regeneration. [8]

Cytokines are a class of proteins that regulates inflammation, cell signaling, and various cell processes such as growth and survival.[9] Chemokines are a subset of cytokines that regulate cell migration, such as attracting immune cells to a site of infection or injury.[9] Various cell types in the brain may produce cytokines and chemokines such as microglia, astrocytes, endothelial cells, and other glial cells. Physiologically, chemokines and cytokines function as neuromodulators that regulate inflammation and development. In the healthy brain, cells secrete cytokines to produce a local inflammatory environment to recruit microglia and clear the infection or injury. However, in neuroinflammation, cells may have sustained release of cytokines and chemokines which may compromise the blood–brain barrier.[10] Peripheral immune cells are called to the site of injury via these cytokines and may now migrate across the compromised blood brain barrier into the brain. Common cytokines produced in response to brain injury include: interleukin-6 (IL-6), which is produced during astrogliosis, and interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), which can induce neuronal cytotoxicity. Although the pro-inflammatory cytokines may cause cell death and secondary tissue damage, they are necessary to repair the damaged tissue.[11] For example, TNF-α causes neurotoxicity at early stages of neuroinflammation, but contributes to tissue growth at later stages of inflammation.

Alzheimer's disease (AD) has historically been characterized by two major hallmarks: neurofibrillary tangles and amyloid-beta plaques.[22] Neurofibrillary tangles are insoluble aggregates of tau proteins, and amyloid-beta plaques are extracellular deposits of the amyloid-beta protein. Current thinking in AD pathology goes beyond these two typical hallmarks to suggest that a significant portion of neurodegeneration in Alzheimer's is due to neuroinflammation.[22][23] Activated microglia are seen in abundance in post-mortem AD brains. Current thought is that inflammatory cytokine-activated microglia cannot phagocytose amyloid-beta, which may contribute to plaque accumulation as opposed to clearance.[24] Additionally, the inflammatory cytokine IL-1β is upregulated in AD and is associated with decreases of synaptophysin and consequent synaptic loss. Further evidence that inflammation is associated with disease progression in AD is that persons that take non-steroidal anti-inflammatory drugs (NSAIDs) regularly have been associated with reduced AD later in life. Elevated inflammatory markers showed an association with accelerated brain aging, which might explain the link to neurodegeneration in AD-related brain regions.[19]

The leading hypothesis of Parkinson's disease progression includes neuroinflammation as a major component.[25] This hypothesis stipulates that Stage 1 of Parkinson's disease begins in the gut, as evidenced by a large number of cases that begin with constipation. The inflammatory response in the gut may play a role in alpha-synuclein (α-Syn) aggregation and misfolding, a characteristic of Parkinson's disease pathology. If there is a balance between good bacteria and bad bacteria in the gut, the bacteria may remain contained to the gut. However, dysbiosis of good bacteria and bad bacteria may cause a “leaky” gut, creating an inflammatory response. This response aids α-Syn misfolding and transfer across neurons, as the protein works its way up to the CNS. The brainstem is vulnerable to inflammation, which would explain Stage 2, including sleep disturbances and depression. In Stage 3 of the hypothesis, the inflammation affects the substantia nigra, the dopamine producing cells of the brain, beginning the characteristic motor deficits of Parkinson's disease. Stage 4 of Parkinson's disease includes deficits caused by inflammation in key regions of the brain that regulate executive function and memory. As evidence supporting this hypothesis, patients in Stage 3 (motor deficits) that are not experiencing cognitive deficits already show that there is neuroinflammation of the cortex. This suggests that neuroinflammation may be a precursor to the deficits seen in Parkinson's disease.[25]

Multiple sclerosis is the most common disabling neurological disease of young adults.[26] It is characterized by demyelination and neurodegeneration, which contribute to the common symptoms of cognitive deficits, limb weakness, and fatigue.[27] In multiple sclerosis, inflammatory cytokines disrupt the blood–brain barrier and allow for the migration of peripheral immune cells into the central nervous system. When they have migrated into the central nervous system, B cells and plasma cells produce antibodies against the myelin sheath that insulates neurons, degrading the myelin and slowing conduction in the neurons. Additionally, T cells may enter through the blood–brain barrier, be activated by local antigen presenting cells, and attack the myelin sheath. This has the same effect of degrading the myelin and slowing conduction. As in other neurodegenerative diseases, activated microglia produce inflammatory cytokines that contribute to widespread inflammation. It has been shown that inhibiting microglia decreases the severity of multiple sclerosis.[25]

Because neuroinflammation has been associated with a variety of neurodegenerative diseases, there is increasing interest to determine whether reducing inflammation will reverse neurodegeneration. Inhibiting inflammatory cytokines, such as IL-1β, decreases neuronal loss seen in neurodegenerative diseases. Current treatments for multiple sclerosis include interferon-B, Glatiramer acetate, and Mitoxantrone, which function by reducing or inhibiting T Cell activation, but have the side effect of systemic immunosuppression [28] In Alzheimer's disease, the use of non-steroidal anti-inflammatory drugs decreases the risk of developing the disease. Current treatments for Alzheimer's disease include NSAIDs and glucocorticoids. NSAIDs function by blocking conversion of prostaglandin H2 into other prostaglandins (PGs) and thromboxane (TX). Prostoglandins and thromboxane act as inflammatory mediators and increase microvascular permeability.

Exercise is a promising mechanism of prevention and treatment for various diseases characterized by neuroinflammation.[20] Aerobic exercise is used widely to reduce inflammation in the periphery. Exercise has been shown to decrease proliferation of microglia in the brain, decrease hippocampal expression of immune-related genes, and reduce expression of inflammatory cytokines such as TNF-α.