Fluorescent tagging of microglia (green) shows intricate processes interacting with neuronal structures (pink) and cell bodies (blue). Image supplied by the Lu Lab, unpublished.
Think of your brain like a bustling city. Neurons – the principle functional cells in the brain – act as roads, carrying important information from one area of town to the other. Like any complex city, the key to efficient transportation is road maintenance and infrastructure. This is where microglia, a supporting brain cell, comes into play.
Like their name suggests, microglia are tiny cells – no larger than 10 microns in length, or the equivalent of one tenth the diameter of a grain of salt. These cells work behind the scenes to ensure healthy neuronal function. Just like construction workers, microglia function to modify neurons and clean up any harmful debris like bacteria, dead cells or faulty neurons, that might affect overall neuronal activity.
Traditionally, brain research has focused on understanding how neurons work. This research is warranted, considering neurons are the basic functional unit of the nervous system, responsible for relaying critical signals throughout the brain that may allow one to think, move, and interact with their surrounding environment. However, neuroscientists are only just starting to understand how microglia support and regulate neuronal function. A recent paper published this year by researchers at Western University in the journal, Glia, presents a new signaling pathway in microglia that has the potential to affect the function of neighbouring cells, including neurons. “Neurons are regulated by glia, and by studying these supporting cells of the brain, we can provide new insight into brain disorders we don’t fully understand,” said lead author Matthew Maksoud, a PhD Candidate in the Graduate Program of Neuroscience at Western University.
Specifically, the research team led by Dr. Wei-Yang Lu proposed a new link between nitric oxide – a well-known mediator of brain inflammation – and microglia’s ability to ‘clean up’ harmful bacteria in the brain. Microglia can remove bacteria through a process called phagocytosis, which results in these cells destroying and engulfing unwanted debris within the brain. The authors showed the ability of a microglial cell to perform phagocytosis relies heavily on the presence of nitric oxide, an inflammatory molecule produced by microglia. “Nitric oxide is an interesting molecule, because in the past it has been looked at as solely detrimental. It’s not that this molecule is negative, but there needs to be a balance.”
3D animation of microglia (green) interacting intricately with neuronal structures (pink). Animation supplied by the Lu Lab, unpublished.
Think back to our city. Microglia work to keep our neuronal ‘roads’ clean and debris-free. An abundance of nitric oxide results in microglia working overtime – over-modifying neuronal structures until they are rendered ineffective. A lack of nitric oxide leads to excessive clutter, again rendering neurons ineffective at transporting signals.
Using various microscopic cellular imaging methods, Maksoud examined phagocytosis in microglia that were unable to produce nitric oxide. Interestingly, microglia lacking nitric oxide production were not as successful in removing bacterial debris compared to normal microglia. Less phagocytosis was not only attributed to decreases in nitric oxide, but also decreased levels of calcium ion channels, which are proteins on the surface of microglia. These calcium ion channels transport calcium in and out of the cell and are necessary for cleaning up those potentially harmful bacteria.
If microglia act as city workers, calcium ion channels work to provide essential resources to microglia, such as the ability to change shape and structure in order to better clean up debris within their environment. Just like nitric oxide, too much or too little calcium ion channel function can overwork or underwork microglia, respectively.
“What we essentially discovered was that two individual processes already known to affect microglia phagocytosis – endogenous nitric oxide production, and a specific calcium ion channel – are actually part of the same signaling pathway,” said Maksoud. “Phagocytosis is such an important part of brain function and dysfunction, so discovering a new mechanism of action can hopefully uncover new ways to modulate microglia function in health and disease.”
This new mechanism behind phagocytosis is just the start of emerging microglia research. With a solid foundation underlying the relationship between nitric oxide and calcium ion channels, Maksoud hopes to see this research field progress using a disease model. “From the literature we also see similar trends with nitric oxide and calcium ion channels in diseases such as brain tumors. Examining this pathway with respect to this type of pathology could be beneficial in uncovering new, potent therapeutic treatments.”
Original Research Article: Maksoud, M. J. E., Tellios, V., An, D., Xiang, Y.-Y., & Lu, W.-Y. (2019). Nitric oxide upregulates microglia phagocytosis and increases transient receptor potential vanilloid type 2 channel expression on the plasma membrane. Glia, 67(12), 2294–2311. https://doi.org/10.1002/glia.23685