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Microglial Brain Cells: How These Once Misunderstood Cells Got Their Time to Shine

An overview of cellular health and microglia 

Our brain is a truly amazing thing – however, it’s something we may often take for granted. Sure, we know it’s responsible for allowing us to experience, perceive and enjoy life. But what’s really going on in there, on a cellular level?  

Today, we’re talking microglia and cellular health.  

Microglia are a form of macrophage immune cell, which are commonly found throughout the body in many different types of tissue and are generally known to facilitate an inflammatory response. Because macrophages are found all over the body, it was originally assumed that microglia in the brain function similarly to macrophages elsewhere. However, this couldn't be further from the truth. 

Microglia were first identified as distinct cells of the central nervous system (CNS) in the 1930s, and are defined by their non-neuronal, non-astrocytic functions. Recent studies have argued against the original view that microglia are simply macrophages of the CNS. In fact, microglia appear to have distinct genetic differences that scientists can use to tell them apart from macrophages and other brain cells. 

Nonetheless, many researchers used to believe that microglia didn’t have a part in key neural functions except for simply cleaning up the garbage from extracellular environments. And at the same time, they believed neurons behaved independently of microglia to communicate with other cells, thereby influencing cognition and behavior.

Because of this, microglia were seen as the “trash collectors” of the central nervous system, where they were primarily involved in the clean-up of cellular debris, dying neurons, and unused synapses. If only those researchers knew what we know now. 

Recent research has shown that a microglial’s job on a garbage truck is simply not true. For example, when microglia were removed from an animal brain, neurons continued to function, but only for a short period of time. Shortly after removal of microglia, however, these neurons quickly spiraled out of control and began to display seizure-like responses. This indicated that microglia had a direct influence on how neurons behaved and communicated. 

To put this in perspective, let’s liken microglia to the brakes of a car moving rapidly downhill. As you move forward, applying the brakes keep the car at a safe speed, ensuring both you, and the car, remain safe and intact when you reach the bottom of the hill. Microglia function very similarly—as neurons fire, microglia appear to moderate the activity of these neurons, ensuring they remain intact and continue to send important messages. However, in the instance of brake failure, the car remains functional only for a short amount of time until it reaches the bottom of the hill at maximum speed. This leaves the car in an unpredictable, dangerous state once it reaches its destination with no control and lots of destructive momentum.  

This is sort of out how microglia appear to control the activity of neurons; without them, neurons progressively increase their activity to a point where they're out-of-control and can become toxic to the surrounding neural environment. The result of microglial loss is a toxic rampage of neurons that can lead to neuronal death and overactive electrical activity in the brain, which can permanently damage the ability of neurons to communicate to one another (which may be a key regulator of neurodegenerative disease).  

Indeed, microglia have come a long way from being simple trash collectors to being known as regulators of neural activity and behavior. This example demonstrating the necessity of microglia to neurons has hopefully carved out the importance of these particular cells in the maintenance of cellular and behavioral health.

In fact, the same researchers mentioned above support the idea that reduced or impaired microglial function may be connected to many neurodegenerative diseases like Alzheimer’s and Huntington’s Disease. As such, targeting microglia may be a reasonable approach to boost protection of sensitive brain circuits implicated in age-related disease. 

Microglial activity is influenced by cellular environments 

Given their prominent role in influencing neuron behavior and communication, you may have already guessed that cellular health (and the external environment) is exceptionally important in the maintenance of microglial function, which in turn, maintains neuronal function. 

Because microglia are highly responsive to the cellular environment, it is important to pay attention to what happens to microglia in different environmental conditions. Doing so can help you understand why brain research specialists believe that an imbalance of microglial responses may be a key risk factor for many age-related and neurodegenerative diseases. 

Microglia tend to convert to what’s known as M1 or M2 phenotypes in response to the cellular environment, and each of these play different roles in regulating CNS health and function. 

M1 microglial functions 

M1 microglia are typically activated by immune stimulants, like pathogens and cellular damage. As a result, M1 microglia release compounds that promote inflammation such as pro-inflammatory cytokines. If left unchecked, these types of cytokines can wreak havoc in the brain by changing the way neurons communicate and impacting mechanisms that normally maintain neuron health. In turn, unchecked M1 microglial activity can affect several different brain-related processes like behavior, emotion, and motivation.  

Importantly, M1 microglia express enzymes that mediate the production of reactive oxygen species (ROS) and other chemicals typically known for their ability to damage neurons. Thus, if M1 microglia remain active for too long, there is potential for ROS to buildup in cells and increase inflammation and neuronal damage. This, together with M1-type microglia releasing inflammatory molecules themselves, presents a recipe for neuronal disaster. 

diagram of unactivated and activated microglial cells and neurons

M2 microglial functions 

Under normal circumstances, microglia in the M2 phenotype behave in a way that protects the brain and CNS from extra clutter and damage. More specifically, M2 microglia will promote a cellular process called phagocytosis, which put plainly, means "cell eating." When this happens, microglia program themselves and others to “eat” or remove clutter and debris away from the extracellular space. These may be things like misfolded proteins or other damaged biological elements that otherwise serve no purpose and would be damaging to normal cellular health. To work toward balance, M2 microglia also release anti-inflammatory cytokines, which helps maintain the immune response and controls inflammation produced by M1 microglia. 

They also help repair and reconstruct the extracellular matrix, which is a fine network of cellular proteins that holds everything together in web-like fashion. We can think of this web-like infrastructure as the frame of a house. While the frame itself is not normally what we look at when we view homes, it still serves a foundational purpose—it creates a structure that holds the house together. The extracellular matrix functions in a similar way.

We often forget to think about how everything in the body is held together so elegantly, but it can absolutely be attributed to the extracellular matrix. As expected, M2 microglia play a big role in repairing the matrix and surrounding tissue. In other words, M2 microglia are your handy service technicians that come to repair defects in the foundational elements of your home.  

Finally, M2 microglia are known for their supportive role in neuron survival. Not only do they help maintain a healthy extracellular environment, but they also play a direct role in ensuring neurons receive the molecular compounds they need to survive and grow.

For example, brain-derived neurotrophic factor (or BDNF), is a key molecule that neurons need when undergoing repair or when they grow connections with other neurons. Importantly, an increase in microglial activity, particularly M2-type microglia, is associated with an increase in BDNF. It’s been proposed that M2 microglia help neurons grow by facilitating the release of BDNF and other factors involved in neuronal survival. This is only one way that M2 microglia have been linked to neuroprotection and neuron viability. 

It's all about balance…of M1/M2-type microglia 

To tie things together, we must understand that M1 and M2-type microglia are not static. They do not simply form as M1 or M2 phenotypes from the early stages of life and then continue to live as such. Instead, microglia may flip back and forth between these phenotypes given the status of the cellular environment.  

So, under circumstances where the cellular environment is threatened, like when a virus triggers an immune response, dormant (non-active) microglia will convert to M1 phenotype and generate inflammatory compounds that are necessary to kill off intruding viral particles. Of course, byproducts like ROS and other neurotoxic compounds are generated, in part, because the molecular processes required to trigger an immune response are energy-demanding. And anything that requires a lot of energy will generate free radicals (for more context, check out our article on the relationship between cells and inflammation).

These M1-type microglia may either continue to function as such, or they may switch to M2-type microglia where they begin to control the inflammation they initially released. All of this is part of microglia’s salute to maintaining a healthy cellular environment for neurons to thrive in and communicate effectively. 

Importantly, because the cellular environment is constantly changing, microglia tend to play on both sides of the field in that they exhibit both M1 and M2 phenotype characteristics. This is necessary in order to maintain the delicate balance between both types of microglia in the CNS and regulate neuroinflammation, which can often be detrimental if it becomes chronic.

Do your microglia a favor by reducing the amount of stress you experience, eat a healthy, nutritious diet, and engage in regular physical activity. All of these practices can promote a healthy cellular environment, thereby encouraging non-inflammatory microglial responses. 

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