Fc gamma receptor IIa signaling from spinal cord astrocytes promotes neuropathic pain in rats

Injury to somatosensory nerves can lead to neuropathic pain. We recently identified that B cells play a crucial role in the development of neuropathic pain through a mechanism involving secreted immunoglobulin G (IgG) signaling at Fc gamma receptors (FcγRs). Here, we demonstrate that Fc gamma receptor IIa (FcγRIIa), expressed by astrocytes in the spinal cord, contributes to the development of mechanical allodynia after nerve injury in male and female rats. Following unilateral chronic constriction injury (CCI) of the sciatic nerve, Fcgr2a gene transcription increased specifically in the ipsilateral dorsal horn of the spinal cord, but remained unaltered in the dorsal root ganglia (DRGs) and contralateral spinal cord. FcγRIIa immunoreactivity increased in the ipsilateral spinal dorsal horn after CCI, and its expression colocalized primarily with GFAP⁺ astrocytes. Genetic disruption of Fcgr2a in GFAP-expressing spinal astrocytes using adeno-associated virus (AAV)-mediated CRISPR-Cas9 gene editing attenuated mechanical allodynia for weeks after CCI. In purified cultures of primary astrocytes, IgG immune complexes (IgG-IC) increased transcription of proinflammatory cytokines and chemokines. Expression of these cytokines and chemokines was reduced by siRNA-mediated knockdown of Fcgr2a, or by inhibition of the FcγRIIa effectors spleen tyrosine kinase (Syk) or nuclear factor-κB (NF-κB). These data suggest that FcγRIIa expressed by spinal astrocytes are activated following peripheral nerve injury and may directly contribute to injury-induced tactile pain through the release of proinflammatory mediators. These findings expand our understanding of how neuroimmune signaling from astrocytes contributes to the development of mechanical allodynia.

Perspective

Activation of FcγRIIa signaling in spinal astrocytes promotes mechanical allodynia following nerve injury and initiates neuroinflammatory pathways in response to IgG immune complexes. These findings reveal autoantibody IgG signaling at glial Fcγ receptors as a potential therapeutic approach to alleviate neuropathic pain.