Microglia, the immune cells of the brain, are essential for sculpting neural circuits by clearing away excess neurons and cellular debris during the brain development.

Remarkably, new research reveals that microglia not only consume dead or dying neurons but also cannibalize other microglia. This self-devouring cycle results in a form of highly inflammatory cell death known as necroptosis.

The study
The study employed advanced techniques, including fluorescence and photoconvertible markers, to uncover this cannibal behavior. These tools allowed researchers to visualize microglia shrinking, bursting, and being consumed by neighboring cells.

Using zebrafish models with fluorescently tagged microglia, scientists observed that as microglia proliferate during early development, some cells die in a dramatic manner, leaving behind cellular remnants that are quickly engulfed by neighboring microglia. This process ensures the careful regulation of microglial populations while maintaining the delicate environment of the developing central nervous system.

The study showed that this microglial death primarily occurs through necroptosis, even when apoptosis, a more controlled form of cell death, was inhibited.

The findings raise intriguing questions about the regulation of microglia during brain formation. Traditionally, the presence and number of microglia have been thought to result from their migration and proliferation within the developing brain.

However, the idea that microglia also actively regulate their numbers by eliminating other microglial cells suggests a more complex control mechanism.

So, inflammation in the brain?
This inflammatory mechanism, necroptosis, is generally linked to strong immune responses that are traditionally considered to be damaging. This study indicates that this particular inflammatory process could serve to tightly regulate microglial populations while preventing unwanted cellular interactions.

This unexpected form of cell death might also act as a safeguard against the promiscuous engulfment of healthy cells, ensuring that the developing brain remains stable.

Beyond development, microglial cannibalism may have broader implications for brain health. For example, in diseases like Alzheimer’s, microglia cluster around plaques, behaving abnormally. Similar processes of inflammatory cell death might contribute to disease progression, making these mechanisms potential therapeutic targets.

Interestingly, microglial necroptosis has been linked to successful brain repair in demyelination models, suggesting that this seemingly destructive process may also play roles in regeneration and maintenance.

This discovery opens up exciting avenues for research into how microglia manage their numbers and contribute to brain development and disease. Understanding these processes may ultimately lead to novel treatments aimed at modulating microglial behavior, particularly in diseases associated with inflammation and cell death.

About the scientific paper:

First author: F Chris Bennett, USA
Published: PLOS Biology, October 2024
Link to paper: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002869