Enhancing immune cleanup to speed recovery and reduce pain after nerve injury

What is it about?

When peripheral nerves are damaged, immune cells help start inflammation that is needed for repair, but this same inflammation can also cause pain. Normally, once repair is underway, other immune processes switch on to calm inflammation and fully resolve the injury. For reasons that are not fully understood, these calming processes sometimes fail after nerve injury, leading to ongoing inflammation and chronic neuropathic pain. One important calming process is called efferocytosis, where immune cells called macrophages "eat" and digest damaged and dying cells. These dying cells show a molecule called phosphatidylserine on their surface as an "eat me" signal, which is recognized by a receptor on macrophages called MERTK. In this study, we show that after nerve injury, MERTK is cut off (cleaved) from the surface of macrophages, so they no longer recognize these "eat me" signals. As a result, dying cells are not cleared efficiently, more cell corpses build up, and nerve damage and pain are worsened. The accumulated dead cells release molecules that can drive pain, including damage-associated signals such as IL-33 and HSP90, as well as antigens that promote the build-up of IgG antibodies at the injury site and in the dorsal root ganglia. When we prevent MERTK from being cleaved in mice, macrophages clear dying cells more efficiently, inflammation is better controlled, nerve structure is preserved, and recovery from pain is faster.

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Photo by Bhautik Patel on Unsplash

Photo by Bhautik Patel on Unsplash

Why is it important?

Chronic neuropathic pain is a common and debilitating condition, and current treatments often do not work well or have serious side effects. This study identifies impaired efferocytosis - specifically, the cleavage of the macrophage receptor MERTK - as a previously unrecognized driver of ongoing inflammation, nerve damage, and pain after peripheral nerve injury. The findings suggest that boosting the clearance of dead and dying cells at the injury site could accelerate nerve repair, limit autoimmune-like antibody build-up, and reduce pain, pointing to new therapeutic strategies for neuropathic pain.

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