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Understanding Microglia Activation – A Tutorial

For a moment, imagine that you are a mechanical engineer with a bachelor degree dealing in mass, spring,

damper, gear and disk, turbine and combustion engine or thermal cycles, general formulas and

mechanical concepts. Now, you are asked: what’s your idea about brain?? What?? There is no more gear

or bearings there! Take it easy!

Here is a world where you are so amateur with all your information. This was my description.

If you are going to read this tutorial to find out, exactly pointing out where I was! So do not be afraid. I’ll

tell you that you understand me too. As simple as possible ;)

The material in this tutorial is based on standard curriculum of K. N. Toosi University of Technology, Faculty

of Electrical Engineering. For more information please contact Faezeh Ibrahimi: faza.ibrahimi@gmail.com

Microglia-why is it important?

Protecting and maintaining everything at a glance is a logical thing. Well, your body is also worth it!

So its safety and maintenance should be respected. This is done without your intervention. These support

cells are called glia cell in the central nervous system and satellite cell in the peripheral nervous system.

Glial cells are approximately 10 times more plentiful than neurons in the CNS. although they are

approximately one-tenth the size of neurons, glial cells take up equal space. Glia is a Greek term meaning

glue. It means that microglia refer to a small glue.

The tiny microglia and the star-shaped astrocytes remove waste materials that are created primarily when

neurons die.

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Look at the pic below:

Human cell

The above image shows the cells of the human body. But what do u think about your brain?

Brain cells

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Neuron at a glance:

Neuron structure

Your NEURONS need MICROGLIA!

Nervous messages are produced by the central nervous system and sent to the entire body through the

peripheral nervous system. The cells that carry the task of transmitting neural messages are NEUORONS.

If neurons are damaged by inflammation caused by trauma or disturbances in the nervous system,

MICROGLIA will be imported to eliminated inflammation with its main function(macrophage). This small

cells play very important roles in your life. If you don’t believe, just keep reading ;)

Microglial cells could be regarded as invaders of the CNS in charge of debris clearance, just active during

brain injury, infection or degeneration. There is no central nervous system (CNS) pathology without a

microglial response.

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CNS: (Central Nervous System)

The central nervous system consists of the brain and spinal cord. It is referred to as "central" because it

combines information from the entire body and coordinates activity across the whole organism.

In the picture below you can see the CNS’s cell:

Cells in central nervous system

The central nervous system has been thoroughly studied by anatomists and physiologists, but it still

holds many secrets; it controls our thoughts, movements, emotions, and desires. It also controls our

breathing, heart rate, the release of some hormones, body temperature, and much more.

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Embryonic layers and Stem cells:

Embryonic layers and Stem cells

A germ layer is a group of cells in an embryo that interact with each other as the embryo develops and

contribute to the formation of all organs and tissues. The germ layers develop early in embryonic life,

through the process of gastrulation. During gastrulation, a hollow cluster of cells called a blastula

reorganizes into two primary germ layers: an inner layer, called endoderm, and an outer layer, called

ectoderm. Human is triploblastic, as endoderm and ectoderm interact to produce a third germ layer,

called mesoderm. Together, the three germ layers will give rise to every organ in the body, from skin and

hair to the digestive tract.

This process of neurulation forms the neural tube, which gives rise to the central nervous system. During

neurulation, ectoderm also forms a type of tissue called the neural crest, which helps to form structures

of the face and brain. Only nerve cells that do not have an ectodermic origin are microglia. In

developmentally mature organism microglia also can be generated from white blood cells known as

monocytes that circulate in the blood and move into the central nervous system. Some sources indicate

that microglia origin is endoderm.

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Microglia subtypes and another neuro cell:

Microglia subtypes and another neuro cell

For many years the function of microglia was unclear. However, today it is known that these cells mediate

immune responses in the central nervous system by acting as macrophages, clearing cellular debris and

dead neurons from nervous tissue through the process of phagocytosis. (cell eating.)

If damage has occurred, microglia are also capable of a sophisticated range of responses depending on

the level of damage. If the damage is small, cells can send out a “find me” signal. The microglia are

activated to a protective state and seek out these cells. They attempt to stabilize the damage and protect

the nearby neurons. However, if the damage is greater or more dangerous to surrounding tissue, these

cells will send out an “eat me” signal. The microglia then become fully activated to a toxic state. They can

kill infected cells before infection spreads and clear any debris from damaged or dying cells.

eat

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Microglia activation:

Microglia Activation

Microglia, the immune cells of the brain, were long thought to be rather boring cells that existed in only

two states — resting and activated. It was long believed that in the healthy brain microglia lay waiting

doing nothing until serious damage was detected. If the brain was infected or damaged, microglia were

thought to respond similarly to the immune cells in the rest of the body swelling, fighting invading micro-

organisms, then returning to a resting state and doing nothing further. However, over the past few years,

increasingly sophisticated experiments have demonstrated that these cells are capable of a wide range of

unexpected activities and responses. As a result, these previously ignored cells are turning out to be

promising targets for new drugs to treat a wide range of neurodegenerative disorders.

1.Resting microglia 2.Active microglia

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The various functions of microglia:

diagram showing the various functions of microglia

1. Phagocytosis

Several methods such as electron microscopy, histochemical localization of hydrolytic enzymes and more

have been used to demonstrate the phagocytic activities of the AMCs. In the developing brain, AMCs

(Amoeboid microglial cells) which share the characteristic features of macrophages are often found to be

involved in phagocytosis of degenerating axons and cells.

2. Immune Functions of Microglia

It has been shown that microglia in the CNS not only act as phagocytic cells but are also involved in the

nonspecific inflammation as well as the adaptive immune responses.

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3. Iron Acquisition

In the white matter, iron is first found in microglia and subsequently in oligodendrocytes during

development.

4. Nitric Oxide Production

It has been reported that activated microglia serve as the main source of NO under neuropathological

conditions.

5. Growth Factors

In inflamed CNS, microglial cells are known to secrete TGF-β1, which is involved in regulation of cell

growth, cell differentiation, angiogenesis as well as in immune function.

6. Microglia in Myelination

Microglia has a role in myelination and myelin repair inflammatory demyelination. The up-regulation of

myelin markers in oligodendrocytes by co-culturing them with microglia or by culturing oligodendrocytes

in the microglial conditioned medium.

7. Microglia in Neurogenesis and Astrogenesis

Apart from phagocytic function, microglia may also have a role in neurogenesis and astrogenesis by

regulating the development of neural precursors.

8. Microglia and Synapses

At early postnatal stages microglial cells express thrombospondin (an extracellular matrix protein) that is

able to induce synaptogenesis and absence of which induces dramatic reduction in the number of

synapses. Also mutations for KARAP/DAP12, a protein expressed by microglia, in perinatal stages

influenced synaptic functions and plasticity.

9. Microglia and Vascularization

Microglia which invade the brain prior to vascularization, are often found in close contact with the blood

vessels and this has been correlated with the developmental vascularization of the brain and retina,

which is an extension of the brain.

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Microglia transform:

Microglia transform with time

classically activated, pro‐inflammatory (M1) macrophages serve in the first line of defense of the innate

immune system occurring often within the first few hours or days. This allows for innate immunological

functions. Within injured tissue, microglia exist in various states of activation and retain the capability to

shift their functional phenotype during the inflammatory.

M2 macrophages play a role in allergy response, parasite clearance, inflammatory dampening, tissue

remodeling, angiogenesis, immune regulation and tumor promotion.

Injury‐induced inflammatory processes are dynamic, demonstrating spatial and temporal heterogeneity,

with the possibility that individual cells express transitional phenotypes. It has been suggested that

macrophages transition from a M1 phenotype to a more regulatory or anti‐inflammatory M2 phenotypes

to promote positive functional outcomes and minimize scar tissue formation. (so after inflammation and

inhibition by microglia, transformation M1 to M2 occurs. M2 type Increase.)

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When be older and Disease Occur:

When be older and Disease Occur

Microglia thus must effectively decide whether to protect or destroy cells in response to insults.

Unfortunately, as the brain ages, these cells seem to become less efficient at reacting. The same signal

that induces microglia to a protective state in a young brain may induce a fully activated, toxic state in an

older brain. It appears that in older brains, microglia overreact to damage and disease. Instead of

protecting brain tissue from further damage, they aggravate the problem by becoming fully activated and

attacking healthy brain cells.

Microglia are, therefore, a very interesting target for therapies for all neurodegenerative diseases such as

Parkinson’s Disease, Alzheimer Disease, multiple sclerosis, stroke, and so on. The goal of many scientists

is now to differentiate the types of signals that control the states of activation of microglia and exploit

these in creating new drugs. While calming the microglia into a protective state will not cure the

underlying neurodegenerative disorders, it could slow the damage and disease progression. This may even

help the brain repair some of the damage, recover lost tissue, and ease the symptoms of these diseases.

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Sleep and Near Infrared Light effect on Microglia:

Sleep and Near Infrared Light effect on Microglia

LED light (710 nm) when applied directly to the top of the animal’s cage significantly activated cellular

immunity, reduced microglial activation and lessened brain infarction size as well as produced

improvement in neurological scores in a rat stroke model. This piece of evidence supports the idea that

the anti-inflammatory effects of brain PBM may at least partly be due to its ability to modulate microglial

activity and a subsequent decrease in inflammatory mediators. Brain tissue-specific functional processes

that occur after brain get near infrared light (700-1000 nm) therapy. On a tissue level, NIR therapy can

increase blood flow and angiogenesis, reduce inflammation and help neurons form new connections.

In other hand, sleep deprivation caused increasing in microglia activation. It means that number of

microglia M1 increase. So pro inflammation cell make injury your neurons and decrease neurogenesis. If

you sleep late or a little, your brain faces to disorder. Take care your microglia cell, take care your health.

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Summary:

Microglia is a tiny cell with big task in your brain.

It has 3 major subtypes: 1-resting, 2-activated M1 (pro inflammation), 3-activated M2 (Anti

inflammation).

This cells act as the first line of immune defense by promoting the clearance of damaged cells or

infectious agents with support neuronal survival and regeneration. They classically addressed as the

resident macrophages of the CNS (Central Nervous system).

Only nerve cells that do not have an ectodermic origin are microglia. Probably its origin is endoderm.

They are in resting form and activated by inflammation. For example: If neurons are damaged by

inflammation caused by trauma or disturbances in the nervous system, MICROGLIA will be important

to eliminated inflammation with its main function(macrophage).

It has been suggested that macrophages transition from a M1 phenotype to a more regulatory or anti‐

inflammatory M2 phenotypes to promote positive functional outcomes and minimize scar tissue

formation. (so after inflammation and inhibition by microglia, transformation M1 to M2 occurs. M2

type Increase.)

Unfortunately, as the brain ages, these cells seem to become less efficient at reacting. The same signal

that induces microglia to a protective state in a young brain may induce a fully activated, toxic state

in an older brain. It appears that in older brains, microglia overreact to damage and disease.

sleep deprivation caused increasing in microglia activation. It means that number of microglia M1

increase. So pro inflammation cell make injury your neurons and decrease neurogenesis.

Near Infrared Light (700-1000nm) if set to 710 nm, reduced microglial activation and lessened brain

infarction size as well as produced improvement in neurological scores in a stroke model.

Pictures have been edited here www.draw.io

Take care your Microglia