Reducing IgG Accumulation via Neonatal FC Receptor (FcRn) Blockade Relieves Neuropathic Pain

Authors

Nathan T Fiore
Kendal F Willcox
Dorsa Dayani
Younus A Zuberi
Cobi J Heijnen
Peter M Grace

Publication Date

3-1-2025

Journal

Brain Behavior Immunology

Abstract

Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and IgG deposition induced by CCI. FcRn are prominently expressed on myeloid and endothelial cells and extend the half-life of IgG via pinocytosis and recycling into the extracellular milieu. We show here that administration of the FcRn blocker efgartigimod either 7- or 28-days post-CCI relieved allodynia among both male and female mice, compared to the Fc fragment control. Efgartigimod, administered systemically (intraperitoneal) or to the lumbar region (intrathecal), attenuated mechanical allodynia for at least one month. CCI-induced allodynia was similarly reduced in FcRn-deficient (FcRn-) mice compared to wild-type mice. Biologic inhibition or genetic deletion of FcRn also reduced CCI-induced accumulation of IgG on macrophages and neurons in lumbar DRG, as well as microglia in the lumbar dorsal spinal cord. Expression of the Fc receptor γ subunit (FcRγ) was reduced in efgartigimod-treated or FcRn- mice post-CCI compared to controls. The FcRγ subunit is a key component of Fc gamma receptors (FcγRs), which are activated by IgG immune complexes. In macrophage cultures stimulated by IgG immune complexes, FcRn blockade also dampened FcγR-dependent production of proinflammatory cytokines. Collectively, our study demonstrates that FcRn blockade or deletion alleviates mechanical allodynia and reduces IgG accumulation after CCI, attenuating pronociceptive IgG-FcγR signaling around the lumbar region. Strategies to block FcRn and reduce IgG recycling warrant further investigation as potential treatments for IgG-mediated neuropathic pain.

Keywords

Animals, Receptors, Fc, Male, Immunoglobulin G, Female, Histocompatibility Antigens Class I, Mice, Neuralgia, Ganglia, Spinal, Hyperalgesia, Mice, Inbred C57BL, Mice, Knockout, Spinal Cord, Sciatic Nerve, Nerve injury, Pain, Immunoglobulin G, Neonatal Fc receptor, Fc gamma receptor, Efgartigimod, Proinflammatory cytokines, Monoclonal antibody

DOI

10.1016/j.bbi.2025.01.015

PMID

39870199

PMCID

PMC11903150

PubMedCentral® Posted Date

3-13-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes