What are the Types of Neuroinflammation?

By Sarah MooreReviewed by Michael Greenwood, M.Sc.

Neuroinflammation refers to the process whereby the brain’s innate immune system is triggered following an inflammatory challenge such as those posed by injury, infection, exposure to a toxin, neurodegenerative disease, or aging.

Image Credit: Design_Cells/Shutterstock.com

Following activation of the immune response certain biochemical and cellular activities are triggered, which have various physiological, biochemical, and behavioral consequences.

The central nervous system (CNS) is called into action to protect the body against the harm posed to it. This is an essential and innate function the body has developed to protect itself, and under normal circumstances is moderated by microglia that sense milieu modifications that threaten a disturbance to homeostasis.

However, in the face of injury, infection or exposure to a toxin, aging, or neurodegenerative disease, the microglia upregulate inflammatory signals, resulting in neuroinflammation. In this way, the encoded response of the CNS can be protective as intended, but also harmful, as the triggering of an acute inflammatory response can become chronic and injurious.

Neuroinflammation arises in slightly different ways depending on its cause. Below these types of neuroinflammation are discussed, and their specific pathways detailed.

Injury

A knock to the head with enough impact can lead to traumatic brain injury, resulting in the initiation of degenerative reparative mechanisms. The triggering of these pathways alerts the immune system and calls on it to generate an inflammatory response.

Therefore, as a result of head trauma, the immune system begins sending out pro-inflammatory cytokines, such as Il-1β, which can worsen the damage caused by the impact, leading to cell death and DNA fragmentation.

The additional release of TNF-α along with the pro-inflammatory cytokines can sometimes lead to a compromise of the blood-brain barrier, reducing its ability to function as a gateway to the brain, protecting it from toxins.

Spinal cord injury is slightly different, it occurs in three distinct steps. The first step sees the compression or transection of the spinal cord trigger factors such as sodium and calcium ion imbalances, excitotoxicity of glutamates, and damage from free radicals.

The initiation of apoptosis following injury, along with the demyelination of neuronal cells leads to inflammation at the location of the injury. This triggers the second phase, which activates reactive gliosis, edema, cavitation of spinal parenchyma, and can lead to an irrecoverable loss of spinal cord function.

An inflammatory response triggered by a spinal cord injury is linked with the secretion of pro-inflammatory cytokines such as interleukin 1β (IL-1β), Interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), inducible Nitric Oxide Synthase (iNOS), IL-6, and IL-23.

The recreation of these cytokines triggers the activation of local microglia and draws in bone-marrow-derived macrophages, resulting in pathogenesis-related to spinal cord injury.

Peripheral immune response

The blood-brain barrier evolved to protect the brain from toxins that may enter the bloodstream. It is constructed of endothelial cells and astrocytes and forms a physical barrier between the bloodstream and the brain.

Junctions at astrocytes regulate what passes through the barrier, but following injury, this can be damaged, leading to an influx of T cells, B cells, and macrophages into the brain having the impact of worsening inflammation.

Infection

Certain infections caused by viruses, bacteria, fungi, and, occasionally, protozoa or parasites, can cause encephalitis (inflammation of the brain) or meningitis (inflammation of the meninges - the layers of tissue that cover the brain and spinal cord). Each cause of an infection activates a slightly different pathway leading to neuroinflammation.

Aging

Cognitive degradation is often related to aging, but also neurodegenerative diseases (discussed below) have a higher prevalence in the older population, both of which are related to brain inflammation.

Research has shown that a healthy but aging brain has chronically increased levels of pro-inflammatory cytokines and reduced levels of anti-inflammatory cytokines, demonstrating that the factor of age alone is linked with chronic neuroinflammation.

Further research has uncovered that aging brains also have an increased number of activated microglia, a sign of activated immune system response, demonstrating another link between the aging brain and neuroinflammation.

Neurodegenerative disease

Neurodegenerative disease and neuroinflammation are intrinsically linked. Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are all related to neuroinflammation. To begin with, neuroinflammation is considered a major cause of the neurodegradation that is characteristic of AD.

It is believed that those with the disease have an abundance of activated microglia that cannot phagocytose amyloid-beta, which may lead or contribute to plaque accumulation.

Neuroinflammation is seen as a major component of PD. It is believed that inflammatory response in the gut may be linked with the initiation of the disease, leading to inflammation of the brain, particularly of the substantia nigra, and disrupting the production of dopamine, which is characteristic of the disease.

Lastly, neuroinflammation is considered to play a major role in the initiation and progression of MS. Research has shown that the blood-brain barrier becomes disrupted by the presence of inflammatory cytokines, which allows for B cells and plasma cells to enter the central nervous system where they damage the myelin sheath that covers the neurons. This demyelination is a major symptom of the disease.

Psychiatric disease

Finally, there is a large body of evidence elucidating the role of neuroinflammation in various psychiatric illnesses. An emerging theory is that stress plays a key role in initiating the deregulation of the immune system in psychiatric diseases, alongside genetic, epigenetic, and environmental factors. This immune system activation has been seen to cause abnormal neurotransmission, resulting in serotonin deficiency, and the increased production of neurotoxic substances that add to disease progression.

Illnesses such as schizophrenia, autism, depression, and other mood disorders have been linked with inflammation of the brain, however, the exact underlying mechanisms of the relationship are specific to each illness.

Further Reading

• All Immunology Content
• What is Immunology?
• What does it mean to be Immunocompromised?
• Classical Immunology
• The Immunological Functions of Red Blood Cells