Microglia: The sentinels of the central nervous system

Signaling involved in microglia chemotaxis

We all slip and fall or bump our heads, and while our heads are designed to withstand light bumps and taps, this can cause mild damage to the brain tissue. Clearly, this damage requires prompt detection and repair.

Microglia, the immune cells of the brain, constantly survey for signs of damage or infection. Microglia actively send their long, thin, branched processes throughout the brain, collectively scanning the entire brain once every few hours, according to the authors of a recent review published in the Journal of Biological Chemistry.

In this review, the authors, Christian Madry and David Attwell at University College London, “compare the key features of microglial baseline surveillance and targeted motility (chemotaxis), and then describe the receptors and signaling pathways controlling both processes.”Baseline surveillance is modulated by ambient ATP levels. Degrading ATP or blocking ATP receptors leads to shorter, slower fingerlike processes, but the actual nucleotide receptor involved is not yet known.

The authors explain that light-deprived mice, which have reduced neuronal activity, have slower, more branched processes covering more volume. This suggests a biological balancing act influenced by neuronal activity between how fast the fingerlike processes move and how much area they cover.

Fractalkine, a vital cell-signaling protein, is also important in baseline microglial surveillance. Knocking out the receptor for fractalkine slows the rate of brain surveillance by 30 percent without changing the number and length of processes, researchers have found.

Once the microglial processes detect signs of brain damage, they stop randomly searching the surrounding area and immediately move toward the site of injury, isolating and phagocytosing the cellular debris or infectious agent.

Madry and Attwell describe three chemical signals indicating brain damage. The most powerful is ATP, which leaks from damaged cells. Also, fibrinogen leaks from damaged blood vessels, and nitric oxide is released from damaged spinal cord tissue.

Indicative of ATP’s central role in damage-signaling, microglia have many extracellular nucleotide receptors. The most important receptor is P2Y12, which is activated by ADP and triggers a noncanonical phospholipase C-dependent phosphorylation cascade in microglial chemotaxis..

In their review, Madry and Attwell note several unresolved questions in the field: How do surveying microglia know where they have already looked? How do they divide the brain between themselves? How can ATP, which is rapidly hydrolyzed, serve as an effective long-range signal?

By answering these questions and understanding how microglia carry out their vital tasks of brain surveillance and repair, researchers may be able to optimize microglial activity in cases of traumatic brain injury and neurodegenerative diseases.

Mollie Rappe Mollie Rappe is an intern at ASBMB Today and a Ph.D. candidate in biophysics at Johns Hopkins University.