Microglia use local protein translation to fight infection and disease

Researchers at Washington University School of Medicine has shed light on the ability of microglial cells, which are immune cells that protect the brain, to locally translate proteins within their peripheral processes. This process of local protein translation allows microglia to independently perform their functions while creating new proteins at specific sites where they are “ingesting” cells or other targets that are no longer needed in the body.

The researchers compared the complex morphology of brain cells, such as neurons with their numerous processes and synapses, to the challenge of gene expression. The genes that code for the necessary proteins are located in the nucleus, far from the sites where new proteins are required. However, neurons have been found to overcome this challenge by moving the necessary mRNA and translational machinery to the activated synapses. The researchers wanted to investigate whether microglia could also engage in this process of local protein translation within their processes.

Microglia, as the resident immune cells in the brain, perform vital functions such as surveying surrounding cells, pruning excess synapses, and clearing debris from injury or infection through phagocytosis. The researchers hypothesized that this phagocytosis process, similar to synapse strengthening in neurons, also requires new protein production. To confirm their hypothesis, the researchers aimed to observe three key findings.

Firstly, they expected to find mRNA, the instructions for producing new proteins, among microglial processes. They also expected to detect ribosomes, the cellular machinery responsible for protein synthesis, within these processes. Finally, by examining brain slices treated with compounds that highlight new protein translation, they anticipated finding evidence of newly translated protein within microglial processes.

To investigate these aspects, the researchers used biochemical methods to purify fragments from mouse brain samples, enriching for processes of all cell types, including microglia. They then added a genetic tag to ribosomes specific to microglia and sequenced the mRNAs found on these tagged ribosomes. This analysis revealed that the genes translated by microglial processes were primarily involved in phagocytosis, supporting the hypothesis that local protein translation is necessary for this process.

The researchers further demonstrated the importance of translation by blocking protein synthesis using ribosome-blocking drugs. This blockage resulted in the inhibition of phagocytosis in brain slices. Interestingly, when they accidentally severed a single process from a microglia cell during the creation of brain slices, they found that the isolated process could still perform phagocytosis independently, suggesting its ability to function without relying on the cell nucleus.

The study’s findings highlight the dynamic nature of microglial processes, which constantly contact neighboring synapses and cells. The researchers discovered that microglia produce new proteins within their peripheral processes, particularly at sites where they are engaged in phagocytosis. This implies that microglia can execute specific functions in different parts of their cells by locally producing subsets of proteins.

The study expands our understanding of microglial processes and their ability to translate proteins locally, bypassing the need for protein transportation from the cell soma. Future research in this field may uncover more details about microglial processes and protein translation, potentially leading to further discoveries. The researchers are particularly interested in exploring the mechanisms by which microglia localize the necessary RNAs and ribosomes, the signals that trigger local translation during debris sensing, and how this process may be altered in brain diseases.

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