Peripheral Nerve Injury Reduces Macrophage Efferocytosis to Facilitate Neuropathic Pain

Authors

Vipul K Pandey
Tusar K Acharya
Kendal F Willcox
Sandeep Dembla
Ajeena Ramanujan
Anamaria R Grieco
Younus A Zuberi
Rajasekaran Mahalingam
Andrew J Shepherd
Cobi J Heijnen
Peter M Grace

Language

English

Publication Date

1-6-2026

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2511401122

PMID

41481465

PMCID

PMC12773720

PubMedCentral® Posted Date

2-10-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

For reasons not fully understood, proresolving immune processes sometimes fail to engage after peripheral nerve injury (PNI), leading to enhanced neuropathic pain and inflammation. Here, we implicate reduced efferocytosis due to proteolytic cleavage of surface MER tyrosine kinase (MERTK) from macrophages at the site of PNI. After PNI, the proportion of macrophages expressing MERTK progressively decreased, while soluble (cleaved) MER increased. Using male and female knock-in mice encoding cleavage-resistant Mertk, we demonstrated that cleavage of MERTK from macrophages at the PNI site led to exaggerated pain-related behaviors. PNI-induced hyperactivity of TRPV1+ sensory neurons and damage to myelin and myelinated axons was exacerbated by MERTK cleavage. Cleavage of MERTK led macrophages to adopt a proinflammatory phenotype. It also reduced their efferocytotic capacity, increasing accumulation of TUNEL+ (apoptotic) and RIPK3+ (necroptotic) cells at the injury site. The pronociceptive damage-associated molecular patterns (DAMPs) interleukin-33 and heat shock protein-90 were increased, consistent with passive release from uncleared cell corpses. These corpses can also release de novo antigens along with DAMPs to trigger autoimmunity, recently implicated in neuropathic pain through a mechanism involving secretion of immunoglobulin G (IgG). Indeed, MERTK cleavage led to accumulation of IgG at the injury site and dorsal root ganglia. All outcomes were further worsened when Mertk was conditionally deleted from macrophages. Our findings identify cleavage of MERTK from macrophages at the injury site as a pivotal regulator of pronociceptive and tissue-damaging neuroimmune signaling after PNI.

Keywords

Animals, Macrophages, Mice, c-Mer Tyrosine Kinase, Neuralgia, Peripheral Nerve Injuries, Male, Phagocytosis, Female, Sensory Receptor Cells, TRPV Cation Channels, Mice, Inbred C57BL, Ganglia, Spinal, Efferocytosis, TAM receptors, ADAM17, efferocytosis, pain; autoimmunity

Published Open-Access

yes

Recommended Citation

Pandey, Vipul K; Acharya, Tusar K; Willcox, Kendal F; et al., "Peripheral Nerve Injury Reduces Macrophage Efferocytosis to Facilitate Neuropathic Pain" (2026). Faculty, Staff and Student Publications. 5777.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5777