Neurodevelopment's dark side: brain cell cannibalism

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

Now, 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 of the microglia, to uncover their cannibal behavior. These tools allowed researchers to visualize microglia shrinking, bursting, and being consumed by neighboring cells.

Using zebrafish models with fluorescent-tagged microglia, scientists observed that as microglia multiply during early development, some of them die, leaving behind cellular residue that are quickly engulfed by neighboring microglia. This process ensures the careful regulation of the microglial populations while maintaining the delicate environment of the developing central nervous system.

Normally, brain cells die in a very controlled manner called apoptosis. But this study showed that the death of the microglia primarily occurs through necroptosis, a much more dramatic death.

Necroptosis is a type of planned cell death that happens when the usual, controlled way of removing cells doesn’t work. Unlike normal cell death by apoptosis, necroptosis causes the cell to swell, burst, and release its content, which alerts the immune system, aka other microglia, to respond.

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 considered a strong immune response, traditionally considered to be damaging.

This study showed 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 in the brain cells, behaving abnormally. Similar processes of inflammatory cell death might contribute to disease progression, making these mechanisms potential therapeutic targets.

Interestingly, microglial necroptosis has also been linked to successful brain repair in demyelination, suggesting that this process may also play roles in regeneration and maintenance - and not only in destruction and death.

This discovery opens up exciting prospects 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 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