Immune cells are important in regeneration, carrying out numerous tasks and issuing signals in a complex interaction with other cell types to produce coordinated reconstruction after damage. Researchers here find that neutrophils assist in the task of clearing out debris after injury to the nervous system, in addition to the macrophages already known to carry out this task. This may change the focus of a number of efforts to spur greater regeneration by manipulating the behavior of immune cells.
Immune cells are normally associated with fighting infection but in a new study, scientists have discovered how they also help the nervous system clear debris, clearing the way for nerve regeneration after injury. Researchers have now shown that certain immune cells - neutrophils - can clean up nerve debris, while previous models have attributed nerve cell damage control to other cells entirely. "This finding is quite surprising and raises an important question: do neutrophils play a significant role in nerve disorders?" Neutrophils are one of the most common types of immune cells and known to engulf microorganisms, but they are not normally associated with peripheral nerve damage.
Researchers found damaged nerve cells produce a stream of molecular lures that specifically attract neutrophils to injury sites in mice. Damaged mouse sciatic nerves produced hundreds of times the normal amount of two "chemoattractant" molecules, Cxcl1 and Cxcl2, which attach to the surfaces of neutrophils and draw the 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. Without the cellular clearance mechanism, nerves can't properly regenerate after injury.
Previous studies have pointed to immune cells called macrophages as the primary immune cell responsible for engulfing and breaking down nerve debris. The team was studying mice genetically modified to lack a receptor on the surface of macrophages - CCR2 - that helps macrophages hone in on injury sites. "We expected that the clearance would be dramatically inhibited without the receptor. To our amazement, the clearance was unchanged from that in normal mice. The mystery we to solve was how nerve cell debris is cleared in these mutant animals." The experiments included sorting immune cells found at injury sites by molecules on their cellular surfaces, and many hours looking at mouse cells through the microscope. "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, nerve cells could not properly clear debris.
The findings could open the door for new therapeutics designed to help repair nerve cells damaged by neurodegenerative disease. Results from the new study suggest immunostimulant molecules that target neutrophils at nerve injury sites might enhance clean-up and promote nerve cell repair. Immunostimulant molecules are often used to treat chronic infections and immunodeficiencies, but additional studies will be needed to determine their specificity and effectiveness in the context of neuropathies.