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Policing the neural night club: microglia

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Published the 4/14/2021

With astrocytes buzzing around the brain, oligodendrocytes hugging every stranger they meet, and everybody dancing to the beat of neurons, somebody needs to act responsibely and see that nobody gets hurt. Even the greatest parties have their limitations, and there is one constantly occuring in our brains. Microglia is here to see that things don't spiral out of control.


Outsiders


Microglia is the only cell type present in the brain that migrates there during embryonal development. Not being native to the brain, it has remarkable adaptive properties. It originates in early embryogenesis from the yolk sac and is the closest relative to macrophages, T-cells and the rest of the immune system the brain will ever know. And it's doing the jobs of all of them!
With the central nervous system being closed off from the rest of the body via Blood Brain Barrier (or BBB), no external bodies are present after its formation, early in development. Apart form small molecules, neither cells, bacteria and not even some bigger protein can pass through an undamaged BBB.
Nevertheless, microglia scours the brain squeezing through other cells, masterfully maneuvering between them without disturbing their work. Although the BBB prevents most of the infective material (viruses and bacteria) from reaching the vulnerable nervous tissue, some occasionally do slip through security measures. Microglia elimiante them on the spot, recognizing the foreign body and swallowing it.

A force unto themselves

Contrary to other cell lines, microglia don't have their progenitors who can replace missing cells when one of them retires. Instead, their lifespan outlives most of their relative. With no foreign bodies (no infection), they can roam the depths of our brains for years, looking for intruders without any visible change!When they encounter a threat to the central nervous system they will wake up from their stasis-like state and activate, rapidly proliferating to fight the intrusions. Only in the most critical cases, when the BBB is weakened, will they call for help from beyond their domain. In those situations, progenitor cells and macrophages, the body's first immune responders, will fill in the ranks of microglia. When the fight is won, they will escort them all out, even by force if necessary, remaining again the only immune force allowed.




Microglia derived from opossum brains.Credit: Laboratory for Molecular Neurobiology, Department of biotechnology, Rijeka



Many-faced protectors

In order to protect our brains as well as possible, microglia adapt to their surroundings, exhibiting extreme plasticity. Being firm believers in „clothes maketh man“ proverb, microglia dress for their environment. At one point they could be the unrelenting law enforcement, outlawing bacteria and viruses alike, and in the other, a gentle helper with local spillage of signaling molecules from overzealous neurons' synapses. Their phenotype (form) changes accordingly, without disturbance in their genetics, like giving a new suit. They do so by a group of proteins collectively known as a sensome, a sensory group of proteins which allows them to evaluate their surroundings and act accordingly.
Microglia can take the role of neurodegeneration or neuroprotection, based on the sensome's input, giving way to several distinct traits.
Ramified microglia are the dormant ones. They are composed of a small cellular body and long arms (processes) with which they scour their surroundings while staying motionless, looking for any foreign materials or dying cells.
Ameboid microglia roam the vastness of the brain, scavenging stray materials of repurposed or dying cells.


Ameboid rat microglia grown in tissue culture. Credit: Gerry Shaw


When a ramified or ameboid microglia detects a threat, they become activated, thickening and retracting their branches, taking on an ameboid shape, rapidly proliferating and devouring the intruders.
The whole process is neither terminal nor polarizing, but rather a spectrum of state ranging from mild worry to full chemical assault machine, excreting inflammatory factors, communicating with astrocytes and neurons to minimize their threats and damage, all while phagocyting (devouring) viruses and bacteria . Once the activated microglia have eaten their fill of intruders, they are called gitter cells.
Vascular microglia are, as their name implies, stationed close to the blood vessels, regulating the uptake of foreign materials and helping to sustain BBB.

Policing the brain in every form

Apart from devouring intruders, microglia helps with regulation of signaling in non-infected regions of the brain, maintaining homeostasis. They accomplish this with a series of extracellular signaling molecules, each destined for a different receiver: astrocytes, neurons, other microglia, and even outsiders like T-cells and myeloid progenitor cells.
In this communication, they easily sense malfunctioning cells in their surroundings.If they deem a cell irreversibly changed and harmful to the rest of the brain, they can excrete large amounts of hydrogen peroxide and nitric oxide, causing a „respiratory burst“, eliminating the malfunctioning cell. Their vast array of chemical weaponry can also be used to remove branches from nerves near damaged tissue to promote regrowth and remapping of damaged neural circuitry.
In severe cases, some overly active microglia can cause more harm than good with their chemical assault. On rare occasions, they can cause large scale neural damage with a chronic inflammatory response, while they try to hunt down the invading infection. Clinical significance Microglia are still underappreciated and understudied cell line.



Their contribution to the healthy and functioning brain starts in embryogenesis, just after they settle in the central nervous system, and lasts until death. Besides their ability to fend off all infections, their ability to modulate neural pathways is still poorly understood. By accumulation of minor neural damage caused by aging, or by chronic inflammation, microglia can become activated, and cause a number of diseases. On the other hand, inactive or faulty microglia are believed to give rise to Prion disease, Schizophrenia and Alzheimer's disease, indicating that their deterioration and our understanding of it might play a big role in discovery of cures for such states. References 1. Aloisi F (November 2001). "Immune function of microglia".

References :
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4. Gehrmann J, Matsumoto Y, Kreutzberg GW (March 1995). "Microglia: intrinsic immuneffector cell of the brain". Brain Research. Brain Research Reviews.20 (3): 269–87. doi: 10.1016 / 0165-0173 (94) 00015-H. PMID 7550361. S2CID 22708728.
5. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013). "Origin and differentiation of microglia". Frontiers in Cellular Neuroscience. 7: 45. doi: 10.3389 / fncel.2013.00045. PMC 3627983. PMID 23616747.
6. Kierdorf and Prinz, J Clin Invest. 2017; 127 (9): 3201–3209. https://doi.org/10.1172/JCI90602.
7. Pluvinage JV, Wyss-Coray T, et al. (April 11, 2019). "CD22 blockade restores homeostatic microglial phagocytosis in aging brains". Nature. 568 (7751): 187–192. 8. Bibcode: 2019Natur.568..187P. doi: 10.1038 / s41586-019-1088-4.PMC 6574119. PMID 30944478.
Verkhratsky A, Butt A (2013). Glial physiology and pathophysiology. Chicester: John Wiley & Sons. ISBN 978-1118402054. [Page needed]


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