Peripheral nerve injuries may have devastating consequences—the extent of these consequences is determined by the amount of cellular damage, the site of the lesion, the degree of disruption of the connective-tissue sheaths that surround the nerve, the extent of associated injuries (especially vascular injuries) and the age and health of the patient.

In the peripheral nerves, injuries elicit a degenerative process consisting of vigorous responses from non-neuronal cells—this degenerative process is dubbed Wallerian degeneration. The key event in this process is the degeneration of the detached distal axons, which triggers a cascade of reactions leading to the clearing of peripheral nerve axonal and myelin debris, and to the production of an environment that supports axon regrowth for months after injury. In other words, Wallerian degeneration prepares the damaged nerve cells for regeneration.

What are the cell types that clear the axonal and myelin debris after a nerve injury? Until now, macrophages—the big eaters of the immune system—have been considered the primary cell type involved in Wallerian degeneration.

Macrophages are phagocytic cells that not only play a variety of roles in innate and adaptive immune responses, but are also involved in would healing and clearing of cellular debris. “Macrophages clear approximately 2 × 10¹¹ erythrocytes each day; this equates to almost 3 kg of iron and haemoglobin per year that is ‘recycled’ for the host to reuse. This clearance process is a vital metabolic contribution without which the host would not survive. Macrophages are also involved in the removal of cellular debris that is generated during tissue remodelling, and rapidly and efficiently clear cells that have undergone apoptosis.”

However, results from a new study published on October 25, 2017, in the Journal of Neuroscience, show that neutrophils are critical for myelin removal in the clean up of nerve debris. For the study (Neutrophils Are Critical for Myelin Removal in a Peripheral Nerve Injury Model of Wallerian Degeneration), the investigators used a mouse model of sciatic nerve injury. They found that, in this model, damaged sciatic nerve cells produce hundreds of times the normal amount of two “chemoattractant” molecules—the chemokines Cxcl1 and Cxcl2—which attach to the surfaces of neutrophils and draw these immune cells into injured tissue. Once at the injury site, the neutrophils engulf cellular debris caused by the nerve damage, tidying up the area so the cells can repair themselves.

Richard Zigmond, senior author of the study, said in a press release that he and his team members were using genetically modified mice that lack a receptor on the surface of macrophages. This receptor—CCR2—helps macrophages hone in on injury sites. The investigators were interested in studying the clearance of nerve cell debris in these mice. “We expected that the clearance would be dramatically inhibited without the receptor. To our amazement, the clearance was unchanged from that in normal mice”, Zigmond said. Therefore, they decided to find out how nerve cell debris is cleared in these mutant mice.

Jane Lindborg, first author of the study, said in the same press release: “We came up with a list of potential cellular candidates that could be compensating for the loss of these specific macrophages and used several different tests to determine which cells were clearing away the nerve debris after injury.” She added: “Though it turns out that several different cells pick up the slack in the absence of macrophages, it was the neutrophil that emerged as a major contributor to debris removal. We also discovered that when we depleted neutrophils, nerve debris clearance was significantly halted in both normal mice and mice lacking a major population of macrophages.” Without neutrophils, debris could not be properly cleared.

The authors conclude that these findings could open the door for the design of new therapeutic agents that can help repair nerve cells damaged by neurodegenerative disease.