Phagocytic microglia and macrophages in brain injury and repair

In stroke do we even know if the dead neurons are being cleaned up properly?  Or do we need to send maggots in there to do the job? Ask your doctor this simple question.

Phagocytic microglia and macrophages in brain injury and repair

Fang Yu1,2| Yangfan Wang1,2| Anne R. Stetler1,2| Rehana K. Leak3|Xiaoming Hu1,2| Jun Chen1,2This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.1Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA2Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA3Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USACorrespondenceJun Chen, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, University Drive, Pittsburgh, PA 15261, USA.Email: chenj2@upmc.eduFunding informationNIH, Grant/Award Number: NS0105430; VA, Grant/Award Number: 821-RC- NB- 30556, I01BX003377, I01BX003651, I01BX005290 and I01BX005589 

Abstract

 

Aims:  

Phagocytosis is the cellular digestion of extracellular particles, such as patho-gens and dying cells, and is a key element in the evolution of central nervous system (CNS) disorders. Microglia and macrophages are the professional phagocytes of the CNS. By clearing toxic cellular debris and reshaping the extracellular matrix, microglia/macrophages help pilot the brain repair and functional recovery process. However, CNS resident and invading immune cells can also magnify tissue damage by igniting runaway inflammation and phagocytosing stressed—but viable—neurons.

 Discussion:  

Microglia/macrophages help mediate intercellular communication and react quickly to the “find- me” signals expressed by dead/dying neurons. The acti-vated microglia/macrophages then migrate to the injury site to initiate the phago-cytic process upon encountering “eat- me” signals on the surfaces of endangered cells. Thus, healthy cells attempt to avoid inappropriate engulfment by expressing “do not- eat- me” signals. Microglia/macrophages also have the capacity to phagocytose immune cells that invade the injured brain (e.g., neutrophils) and to regulate their pro- inflammatory properties. During brain recovery, microglia/macrophages engulf myelin debris, initiate synaptogenesis and neurogenesis, and sculpt a favorable extracellular matrix to support network rewiring, among other favorable roles. Here, we review the multilayered nature of phagocytotic microglia/macrophages, including the molecular and cellular mechanisms that govern microglia/macrophage-induced phagocytosis in acute brain injury, and discuss strategies that tap into the therapeutic potential of this engulfment process.

 Conclusion: 

 Identification of biological targets that can temper neuroinflammation after brain injury without hindering the essential phagocytic functions of microglia/macrophages will expedite better medical management of the stroke recovery stage.

 KEYWORDS

acute brain injury, brain repair, microglia/macrophage, phagocytosis

The brain needs to 'clean itself up' so that it can 'sort itself out'

In stroke do we even know if the dead neurons are being cleaned up properly?  Or do we need to send maggots in there to do the job? Ask your doctor this simple question. 

The brain needs to 'clean itself up' so that it can 'sort itself out'

A piece of research led by the Achucarro Basque Center for Neuroscience, the University of the Basque Country (UPV/EHU), and the Ikerbasque Foundation has revealed how the brain’s cleaning up mechanisms function in neurodegenerative diseases.
When neurons die, their remains need to be eliminated quickly so that the surrounding brain tissue can continue functioning. A type of highly specialised cell known as microglia is responsible for this process which is called phagocytosis (derived from the Greek “phagein”, to eat, and “kitos”, cell). These tiny cells have numerous branches that are constantly on the move inside the brain and are specially equipped to detect and destroy any foreign element, including dead neurons. Or that is what has been believed until now.
In this study, which has just been published by the journal Public Library of Science (PLoS) Biology, the process of neuronal death and microglial phagocytosis in the diseased brain has been studied for the first time. To do this, brain samples taken from epilepsy patients at the University Hospital of Cruces and from epileptic mice were used.
Neurons are known to die during the convulsions associated with epilepsy. But contrary to expectations, in this condition the microglia are “blind” and incapable of either finding them or destroying them. Their behaviour is abnormal. And the dead neurons that cannot be eliminated build up and damage the neighbouring neurons further, which leads to an inflammatory response by the brain which harms and damages it even further.
This discovery opens up a new channel for exploring therapies that could palliate the effects of brain diseases. In fact, the research group that authored this work is right now exploring the development of drugs to encourage this cleaning up process, phagocytosis, that could help in the treatment of epilepsy patients.
The study was led by Dr Amanda Sierra, head of the Glial Cell Biology laboratory of the Achucarro Basque Center for Neuroscience, and the experimental work was conducted mainly by the researchers Oihane Abiega, Sol Beccari and Irune Díaz-Aparicio. Other Achucarro and UPV/EHU researchers such as Juan Manuel Encinas, Jorge Valero, Víctor Sánchez-Zafra and Iñaki París also participated in it.
This piece of international research was coordinated from the Basque Country and had the participation of research groups from CIC bioGUNE (Derio), the University of Bordeaux (France), the University of Southampton (UK), Université Laval (Canada), and the Baylor College of Medicine (USA).

• Full bibliographic informationO Abiega et al. "Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling" PLoS Biol 14(5): e1002466. doi:10.1371

The brain needs cleaning to stay healthy

In stroke do we even know if the dead neurons are being cleaned up properly?  Or do we need to send maggots in there to do the job? Ask your doctor this simple question.
http://medicalxpress.com/news/2016-05-brain-healthy.html

Research led by the Achucarro Basque Center for Neuroscience, the University of the Basque Country (UPV/EHU), and the Ikerbasque Foundation has revealed the mechanisms that keep the brain clean during neurodegenerative diseases.

When neurons die, their debris need to be quickly removed in order for the surrounding brain tissue to continue to function properly. Elimination of the neuron corpses, in a process called phagocytosis, is carried out by highly specialized cells in the brain called microglia. These small cells have many ramifications that are in constant motion and are specially equipped to detect and destroy any foreign element, including dead neurons. Or so it was thought until now.
This study, publishing May 26, 2016 in PLOS Biology, investigates, for the first time, the process of neuronal death and microglial phagocytosis in the diseased brain. To this end, scientists collected brain samples from epilepsy patients at University Hospital of Cruces and from epileptic mice.
It is known that during epilepsy-associated seizures, neurons die. However, contrary to what happens in the healthy brain, during epilepsy, microglia seem to be "blind" and unable to find the dead neurons and to destroy them. Their behavior is abnormal. Therefore, dead neurons cannot be eliminated and accumulate, spreading the damage to neighboring neurons and triggering an inflammatory response that worsens the brain injury.
This discovery opens a new avenue to explore therapies that could alleviate the effects of brain diseases. In fact, the research group that undertook these studies is currently developing drugs, hoping to boost this cleaning process -phagocytosis- and help in the treatment of epilepsy.

Explore further: Epilepsy has been found to reduce the generation of new neurons

More information: Abiega O, Beccari S, Diaz-Aparicio I, Nadjar A, Layé S, Leyrolle Q, et al. (2016) Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling. PLoS Biol 14(5): e1002466. DOI: 10.1371/journal.pbio.1002466

Journal reference: PLoS Biology
Provided by: Public Library of Science

Maggots make a comeback as a cheap, non-antibiotic treatment for infected wounds

So ask your doctor if your dead area in your brain needs cleaning out by maggots and using trepanation to get there.
http://medcitynews.com/2014/09/maggots-make-comeback-cheap-non-antibiotic-treatment-infected-wounds/?

Efforcytosis

So stump your doctor and ask how this works - efforcytosis.
efferocytosis (from efferre, Latin for 'to take to the grave', 'to bury') is the process by which dying/dead cells (e.g. apoptotic or necrotic) are removed by phagocytic cells. So the extremely serious question for your doctor is; How fast is this process? What will prevent this from cleaning up just minimally damaged neurons? And what is your doctor doing about this problem? ANYTHING AT ALL?
I once asked a doctor if the dead area in my brain would rot, the answer was no, it just turns into CSF - cerebro spinal fluid. I was thinking that maybe I needed maggots or carrion beetles to clean out my brain.

Warfarin-induced skin necrosis diagnosed on clinical grounds and treated with maggot debridement therapy

So ask your doctor if they have maggots on hand in case this side effect occurs.
http://casereports.bmj.com/content/2013/bcr-2012-007455.abstract

Summary

A patient with a history of deep vein thrombosis presented with painful bruising and blistering on his left leg 7–10 days after warfarin treatment. A complicated 2-month treatment followed, where vasculitis was originally diagnosed from histological findings before the final diagnosis of warfarin-induced skin necrosis (WISN) was made on clinical grounds. Warfarin was stopped, reversed and low molecular weight heparin started but, the lesions had progressed to full thickness necrosis. This was originally treated with conventional surgical debridement before introducing maggot debridement therapy (MDT) in an effort to try to salvage the limb.

Maggots can help quicken healing, study shows

For sqeamish  readers, STOP NOW. I once posted the question about whether or not my dead brain area would rot. A doctor replied that it would just turn to cerebrospinal fluid.  I however was thinking of a roommate of mine who was studying bones of dead animals who would be glad to see carrion beetles consuming the dead body, probably similar to maggots. And was envisioning needing to drill a hole(trepanation) in my head to allow these to clean it up.

http://scopeblog.stanford.edu/2012/04/maggots-can-help-quicken-healing-study-shows/
Carrion beetle here:
 http://snailstales.blogspot.com/2008/10/carrion-beetle-nicrophorus-tomentosus.html
maggots here:
http://www.medicalcodingschools.net/blog/7-disgusting-medical-treatments-that-actually-work