1- What Are cytokines?

Cytokines are small proteins that are produced by white blood cells, such as lymphocytes T and lymphocytes B, and endothelial cells, mast cells, fibroblasts, and mesenchymal cells.

In the nervous system, cytokines are produced by microglia, astrocytes, endothelial cells, and macrophages [1].

• Lymphocytes T

Lymphocytes T are immune cells involved in the killing of viruses and cancer cells.

• Lymphocytes B

Lymphocytes B are immune cells that produce antibodies against viruses, bacteria, and cancer cells. Anomalies in the recognition of the body’s own antigens lead to autoimmune diseases.

• Endothelial Cells

Endothelial cells are the building block of vessels.

• Mesenchymal Cells

Mesenchymal Cells are cells that generate connective tissues.

• Fibroblasts

Fibroblasts are cells found in connective tissues where they produce collagen and are also involved in wound healing.

• Mast Cells

Mast cells are found in connective tissues where they produce histamine (neurotransmitter) and heparin (anticoagulant).

• Macrophages

Macrophages are a type of white cells that are responsible for engulfing and digesting viruses, microbes, cancer cells, debris of cells, and foreign substances.

• Microglia

Microglia are non-neuronal cells that are specifically found in the brain and the spinal cord where they play an essential role in the immune response.

• Astrocytes

Astrocytes are also non-neuronal cells responsible for providing nutrients to the nervous system and support the activity of the nervous system endothelial cells in forming the blood-brain barrier.

2- What Are Chemokines?

Chemokines are also cytokines that control the movement of lymphocytes in response to inflammation, infection, or cancer.

3- What Are Secondary Messengers?

When a ligand such as a growth factor, binds to a receptor on the surface of cells in the body there is a transmission of information within the cells by small molecules and ions that promote the expression of proteins necessary for the function of the cell.

4- What Are Reactive Oxygen Species (ROS)?

Reactive oxygen species (ROS) are produced by the metabolism of oxygen (O2) in the body’s cells. An excess of ROS (e.g., free radicals) can damage the DNA of the cells causing their death or mutations that can lead to cancer.

5- What Causes Neuroinflammation?

• Traumatic Brain Injury

A traumatic brain injury can be mechanical such as a blow to the brain or spinal cord leading to tissue damage, or pathological due to tissue damage caused by excitotoxicity (excessive excitation of neurotransmitters), ischemic injury, or alterations in mitochondria function [2].

• Spinal Cord Injury

A spinal injury is due to an acute or localized (focal) trauma, a reduced blood supply (ischemia), or excitotoxicity.

• Infection

The most known infection of the central nervous system (CNS) is due to Mycobacterium tuberculosis (tuberculosis), but there are other infections such as Plasmodium falciparum (malaria), Rickettsia conorii (Boutonneuse fever), Trypanosoma cruzi (Chagas disease) [3].

These infections cause inflammation by altering the function of the CNS vessels.

• Autoimmunity

Autoimmunity is due to the production of antibodies by lymphocytes B against antigens that are expressed by normal cells, including cells of the brain and spinal cord.

These antibodies are known as autoantibodies and attack the body’s cells and tissues causing their damage and inflammation.

• Toxic Metabolites

Alterations in CNS metabolites (Neurometabolites) such as N-acethylaspartate (NAA), creatine, and glutamine can cause injuries or death of neurons in the central nervous system leading to inflammation.

• Aging

Although the mechanisms are not known, there is an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines in the aged central nervous system.

6- What Are the Symptoms of Neuroinflammation?

The symptoms of neuroinflammation depend on the injured part of the central nervous and the type of injury; however, some of the common symptoms are pain, depression, and fatigue.

7- What Mechanisms Mediate Inflammation in the Brain?

The immune response and inflammation in the brain and spinal cord are mainly mediated by microglia and astrocytes but also endothelial cells, and macrophages.

The brain and spinal cord are closed environments due to the presence of the blood-brain barrier (BBB), therefore, not all the cells of the immune system can enter [4].

Following the damage of the brain or spinal cord, microglia are activated and secrete cytokines and chemokines that recruit other cell types such as astrocytes, endothelial cells, and macrophages to repair the damage.

However, during the early stage of spinal injury, there is an infiltration of other immune cells, such as neutrophils, and monocytes. Lymphocytes also contribute to inflammation at a later stage of the injury [1].

9- How Does Neuroinflammation Contribute to Neurodegeneration?

Although the mechanisms are not well known, neuroinflammation has been implicated in the pathogenesis of dementia through its role in cerebral small vessel disease (SVD)-vascular dementia [5].

Neuroinflammation contributes to multiple sclerosis through the disruption of the blood-brain barrier resulting in the recruitment of immune cells and the secretion of proinflammatory factors and antibodies against the myelin sheath.

It was suggested that neuroinflammation also contributes to Alzheimer’s disease through the incapacity of microglia to eliminate amyloid-beta plaques [6].

10- How Is Neuroinflammation Treated?

For multiple sclerosis, a monoclonal antibody (rituximab) has been successfully used to target lymphocytes B responsible for the production of antibodies against the myelin sheet.

However, this treatment has also a potential risk of inducing a rare disease known as progressive multifocal leukoencephalopathy that causes damage to the white matter in multiple parts of the brain [7].

For Alzheimer’s disease and Parkinson’s disease, there are several ongoing clinical trials using inhibitors that regulate the function of microglia and astrocytes which are involved in the pathogenesis of AD and PD [7].

Conclusion

Neuroinflammation is a natural response of the brain and spinal cord to injuries, autoimmunity, infection, toxic metabolites, and aging.

Although its role is to promote the repair of tissues’ damage, proinflammatory cytokines can also result in the recruitment of other types of cells, such as immune cells, fibroblasts, and lymphocytes that can lead to additional and indirect tissue damage resulting in neurodegenerative diseases such as dementia, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

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