Peripheral nerve injury reduces macrophage efferocytosis to facilitate neuropathic pain

Area of Science:

• Neuroimmunology
• Molecular Medicine
• Pain Research

Background:

• Proresolving immune processes are crucial for recovery after peripheral nerve injury (PNI).
• Failure of these processes can lead to chronic neuropathic pain and inflammation.
• The precise mechanisms underlying this immune failure remain incompletely understood.

Purpose of the Study:

• To investigate the role of MER tyrosine kinase (MERTK) cleavage in macrophage efferocytosis following PNI.
• To determine the impact of MERTK cleavage on neuropathic pain, neuroinflammation, and tissue damage.
• To elucidate the downstream consequences of MERTK cleavage on immune cell phenotypes and signaling.

Main Methods:

• Utilized knock-in mice with cleavage-resistant Mertk and conditional Mertk deletion in macrophages.
• Assessed pain-related behaviors, sensory neuron activity (TRPV1+), and axonal damage post-PNI.
• Quantified efferocytosis, macrophage phenotype, and accumulation of apoptotic/necroptotic cells.
• Measured levels of damage-associated molecular patterns (DAMPs) and immunoglobulin G (IgG).

Main Results:

• PNI led to decreased MERTK expression and increased soluble MERTK, indicating cleavage.
• MERTK cleavage exacerbated pain behaviors, sensory neuron hyperactivity, and nerve damage.
• Cleaved MERTK induced a proinflammatory macrophage phenotype, reduced efferocytosis, and increased cell corpse accumulation.
• MERTK cleavage elevated pronociceptive DAMPs (IL-33, HSP90) and IgG deposition at injury sites and dorsal root ganglia.

Conclusions:

• Proteolytic cleavage of MERTK from macrophages is a key mechanism impairing efferocytosis after PNI.
• MERTK cleavage drives neuropathic pain and tissue damage by promoting inflammation and autoimmune responses.
• Targeting MERTK cleavage represents a potential therapeutic strategy for managing neuropathic pain.