Neuroinflammation

Source: Wikipedia, the free encyclopedia.

Neuroinflammation is

glial cells expressing major histocompatibility complex molecules, perpetuating the immune response.[4] Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.[2]

Causes

Neuroinflammation is widely regarded as chronic, as opposed to acute, inflammation of the

neurodegenerative diseases
. Common causes of chronic neuroinflammation include:

The initiation of neuroinflammation in the body. (Created with BioRender.com)

Viruses, bacteria, and other infectious agents activate the body’s defense systems and cause immune cells to protect the designed area from the damage. Some of these foreign pathogens can trigger a strong inflammatory response that can compromise the integrity of the blood-brain barrier and thus change the flow of inflammation in nearby tissue. The location along with the type of infection can determine what type of inflammatory response is activated and whether specific cytokines or immune cells will act.[7]

Neuroimmune response

See also: Neuroimmune system

Glial cells

Microglia are recognized as the innate immune cells of the central nervous system.[2] Microglia actively survey their environment and change their cell morphology significantly in response to neural injury.[8] 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.[8]

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 is in fact beneficial for axonal regeneration.[9]

Cytokines

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.[12] For example, TNF-α causes neurotoxicity
at early stages of neuroinflammation, but contributes to tissue growth at later stages of inflammation.

Peripheral immune response

The

B cells
, may then enter into the brain. This exacerbates the inflammatory environment of the brain and contributes to chronic neuroinflammation and neurodegeneration.

Traumatic brain injury

leukocytes.[13] Increased density of activated immune cells have been found in the human brain after concussion.[1]

As the most abundant immune cells in the brain, Microglia are important to the brain’s defense against injury. The major caveat of these cells comes from the fact that their ability to promote recovery mechanism with anti-inflammatory factors, is inhibited by their secondary ability to make a large amount of pro-inflammatory cytokines. This can result in sustained brain damage as anti-inflammatory factors decrease in amount when more pro-inflammatory cytokines are produced in excess by microglia. The cytokines produced by microglia, astrocytes, and other immune cells, activate glial cells further increasing the number of pro-inflammatory factors that further prevent neurological systems from recovering. The dual nature of microglia is one example of why neuroinflammation can be helpful or hurtful under specific conditions.[14]

Role of Neuroinflammation in the Pathophysiology of TBI. (Created with BioRender.com)

Spinal cord injury

free radical damage.[16] Neurodegeneration via apoptosis and demyelination of neuronal cells causes inflammation at the injury site.[15] This leads to a secondary SCI, whose symptoms include edema, cavitation of spinal parenchyma, reactive gliosis, and potentially permanent loss of function.[15]

During the SCI induced inflammatory response, several pro-inflammatory cytokines including

tumor necrosis factor α (TNFα) are secreted, activating local microglia and attracting various immune cells such as naive bone-marrow derived macrophages.[17]
These activated microglia and macrophages play a role in the pathogenesis of SCI.

Upon infiltration of the injury site's epicenter, macrophages will undergo phenotype switching from an M2 phenotype to an M1-like phenotype. The M2 phenotype is associated with anti-inflammatory factors such as IL-10, IL-4, and IL-13 and contributes to wound healing and tissue repair. However, the M1-like phenotype is associated with pro-inflammatory cytokines and reactive oxygen species that contribute to increased damage and inflammation.[18] Factors such as myelin debris, which is formed by the injury at the damage site, has been shown to induce the phenotype shift from M2 to M1.[19] A decreased population of M2 macrophages and an increased population of M1 macrophages is associated with chronic inflammation.[19] Short term inflammation is important in clearing cell debris from the site of injury, but it is this chronic, long-term inflammation that will lead to further cell death and damage radiating from the site of injury.[20]

Aging

long term potentiation (LTP) in the hippocampus and thereby reduce the ability to form memories.[24]

Impairment of neuron LTP by activated Microglia. (Created with BioRender.com)

As one of the major cytokines responsible for maintaining inflammatory balance, IL-6 can also be used as a biological marker to observe the correlation between age and neuroinflammation. The same levels of IL-6 observed in the brain after injury, have also been found in the elderly and indicate the potential for cognitive impairment to develop. The unnecessary upregulation of IL-6 in the elderly population is a result of dysfunctional mediation by glial cells that can lead to the priming of glial cells and result in a more sensitive neuroinflammatory response.[25]

Role in neurodegenerative disease

Alzheimer's disease

non-steroidal anti-inflammatory drugs (NSAIDs) regularly have been associated with a 67% of protection against the onset of AD (relative to the placebo group) in a four-year follow-up assessment.[29] Elevated inflammatory markers showed an association with accelerated brain aging, which might explain the link to neurodegeneration in AD-related brain regions.[22]

Parkinson's disease

The leading hypothesis of

gut, as evidenced by a large number of cases that begin with constipation[citation needed]. The inflammatory response in the gut may play a role[citation needed] 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.[citation needed] 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.[30]

Amyotrophic lateral sclerosis

Unlike other neurodegenerative diseases, the exact pathophysiology of

amyotrophic lateral sclerosis (ALS) is still far from being fully uncovered. Several hypotheses have been proposed to explain the development and progression of this lethal disease,[31] by which neuroinflammation is one of the above. It is characterised by the activation of microglia and astrocytes, T lymphocyte infiltration, and the production of pro-inflammatory cytokines.[32] Features of neuroinflammation were observed in the brain of living ALS patients,[33] post-mortem CNS samples,[34] and mouse models of ALS.[35] Multiple evidence has described the mechanism of how microglial and astrocyte activation can promote disease progression (reviewed by [36][37]). Replacement of mSOD1 microglia and astrocytes with the wild-type forms delayed motor neuron (MN) degeneration and extended the lifespan of ALS mice.[38][39] Infiltration of T cells was reported in both early and late stages of ALS.[38][40][41] Among all T cells, CD4+ T cells has drawn the most attention by being a neuroprotective agent during MN loss.[42] T regulatory (Treg) cells is also a safeguard against neuroinflammation, demonstrated by the evidence of inverse correlation of the number of Treg cells and disease progression/ severity.[38][43] Apart from the three phenotypes discussed, peripheral macrophages/ monocytes and the complement system are also suggested to be contributed to disease pathogenesis. Activation[44] and invasion[45][46] of peripheral monocytes observed in the spinal cord of ALS patients and mice may lead to MN loss. Expression of several complement components are reported to be upregulated in the samples isolated from ALS patients[47] and transgenic rodent models.[48]
Further studies are required to elucidate their roles in ALS.

Multiple sclerosis

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.[30]

Role as a therapeutic target

Drug therapy

Because neuroinflammation has been associated with a variety of neurodegenerative diseases, there is increasing interest to determine whether reducing inflammation will reverse

prostaglandins (PGs) and thromboxane
(TX). Prostoglandins and thromboxane act as inflammatory mediators and increase microvascular permeability.

Exercise

TNF-α
.

The neuroprotective and anti-inflammatory effects of exercise on cognitive diseases.

Exercise can help protect the mind and body by maintaining the brain’s internal environment, focusing on recruiting anti-inflammatory cytokines, and activating cellular processes that proactively protect against damage while also initiating recovery mechanisms. The ability of physical activity to stimulate immune defenses against neuroinflammation-related diseases has been observed in recent clinical studies. The application of various exercises under a range of different conditions resulted in higher neurological metabolism, stronger protection against free radicals, and stronger neuroplasticity against neurological diseases. The resulting increase in brain function was due to the induced change in gene expression, increase in trophic factors, and reduction in pro-inflammatory cytokines.[53]

References

  1. ^ a b c Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS et al. Molecular imaging of neuroinflammation in patients after mild traumatic brain injury: a longitudinal 123 I-CLINDE SPECT study. Eur J Neurol 2019. doi:10.1111/ene.13971.
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Further reading

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