Neuroinflammation

Anatomy

Neuroinflammation is an inflammatory reaction that takes place in the brain in which molecules called cytokines are expressed.

Tissues react in response to infection or the presence of a foreign body: this inflammatory reaction is characterized by redness or functional damage.

The actors participating in these phenomena are the white blood cells (called leukocytes) produced by the bone marrow and present in the blood.

The number of leukocytes increases during inflammation.

There are three main classes of white blood cells: lymphocytes, granulocytes and monocytes.

  • Lymphocytes participate in the immune response by producing antibodies that will help destroy the pathogen (eg bacteria).
  • Granulocytes which are white blood cells qualified as “non-specific” for an antigen.
  • Monocytes are blood cells which phagocytose (from the Greek phagos, to eat; phagocytosis was demonstrated at the beginning of the 20th century by the Russian biologist Elie Metchnikoff), that is to say, they swallow and digest cellular debris and living particles (eg microbes).

There is another type of “devouring” cells with the same properties as monocytes: these are macrophages (from the Greek makros, large). While monocytes are found specifically in the blood, macrophages are located in tissues.

There are thus macrophages in the brain which bear the name of microglial cells: they form with astrocytes and oligodendrocytes glial cells (read the article on (article on the functioning of the brain).

Can the brain be the target of inflammation?

It was believed until recently that the brain enjoyed – unlike other organs – an immune privilege and largely escaped immune surveillance. It is not so.

In this respect, the microglial cell plays an obviously central role since it is the cell which phagocyte foreign elements. But it can also turn against neighboring cells, that is to say neurons, especially during neurological disorders. It’s sort of Dr. Jekyll and Mr. Hyde.

Alzheimer’s disease is therefore accompanied by activation of microglial cells. This reaction causes an inflammatory reaction called neuroinflammation, in which a good hundred different molecules are expressed, called cytokines.

Cytokines

The hallmark of an immune reaction and neuroinflammation is the production of cytokines (from the Greek kutos, cell, and kineo, stimulate), chemical messengers that allow cells to communicate with each other.

They are therefore released by glial cells when an infectious or toxic agent attacks the body.

The cytokines will thus induce, control or inhibit the intensity and duration of the immune response. When cytokines are secreted by cells, they work:

  • circulating in the blood (this is the endocrine mode, from the Greek endon, inside; ekkrinein, to excrete),
  • by acting on the cells which secrete them themselves (this is the autocrine mode, from the Greek auto, in itself) or
  • by acting on neighboring cells (this is paracrine fashion, from the Greek para, next to).

They are involved in a large number of functions, in particular in resistance to infectious or toxic agents. They therefore encompass several fields of application: oncology, hematology, immunology, infectiology and neurology. There are around forty cytokines identified to date, grouped into families. Those playing a role in brain disorders are:

– Interleukins (IL) such as interleukin 1 (IL-1).

– Le transforming growth factor-ß.

– Tumor necrosis factor (or TNF-alpha for tumor necrosis factor-alpha).

Numerous studies have shown that many attacks on the brain from head injuries, strokes, infections or certain mental illnesses (schizophrenia, Alzheimer’s disease) are associated with high concentrations of cytokines (for example IL -1 or TNF-alpha).

This phenomenon of overproduction of cytokines in the brain is called  neuroinflamation.

Neuroinflammation is involved in Alzheimer’s disease

Neuroinflammation is therefore characterized by an increased release of certain cytokines in the brains of patients with Alzheimer’s disease (AD). One of these cytokines is thought to be particularly involved in AD: TNF-alpha. Indeed :

– TNF-alpha levels are 25 times higher in cerebrospinal fluid (the fluid in which the brain bathes) of AD patients than in healthy people; in addition, patients with mild cognitive decline and high TNF-alpha levels have an increased risk of developing AD.

– Genetic polymorphisms * associated with an increase in TNF-alpha production have been observed in certain populations at an increased risk of developing AD.

* Genetic polymorphisms: a gene has two copies called alleles. These alleles can exist in different forms in a population: this is polymorphism. This difference in expression does not cause disease but can increase the risk of developing it.

– According to an epidemiological study, production of TNF-alpha by blood cells (macrophages, mast cells) is associated with an increased risk of developing AD.

– The studies carried out in animals reinforce the hypothesis of a role of TNF-alpha in the dysfunction of synapses (contact zones between neurons) during pathological aging; particularly when synapses are exposed to amyloid, a protein that plays an inhibitory role in memory and in neuronal death in AD.

TNF-alpha and amyloid have also been shown to enter a vicious cycle in which amyloid stimulates microglial cells, which excites neurons and glial cells, which make more amyloid, and so on. following.

TNF-alpha and Alzheimer’s disease

The excess TNF-alpha produced by macrophages will cause an excessive inflammatory reaction which will damage the joints and cause inflammatory rheumatism such as rheumatoid arthritis. Molecules capable of blocking the action of TNF-alpha have already been developed in the treatment of this disease. These molecules are: etanercept, infliximab and adalimumab. Based on these results, the medical community set out to test one of these molecules in Alzheimer’s patients.