Lacagnina Michael J, Willcox Kendal F, Fiore Nathan T, Grieco Anamaria R, Li Jiahe, Heijnen Cobi J, Grace Peter M
Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Pain. 2025 Sep 11;36:105553. doi: 10.1016/j.jpain.2025.105553.
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.
躯体感觉神经损伤可导致神经性疼痛。我们最近发现，B细胞通过一种涉及分泌型免疫球蛋白G（IgG）在Fcγ受体（FcγRs）处信号传导的机制，在神经性疼痛的发生发展中起关键作用。在此，我们证明脊髓星形胶质细胞表达的Fcγ受体IIa（FcγRIIa）在雄性和雌性大鼠神经损伤后机械性异常性疼痛的发生中起作用。坐骨神经单侧慢性压迫损伤（CCI）后，Fcgr2a基因转录在脊髓同侧背角特异性增加，但在背根神经节（DRG）和对侧脊髓中保持不变。CCI后，FcγRIIa免疫反应性在脊髓同侧背角增加，其表达主要与GFAP星形胶质细胞共定位。使用腺相关病毒（AAV）介导的CRISPR-Cas9基因编辑对表达GFAP的脊髓星形胶质细胞中的Fcgr2a进行基因破坏，可在CCI后数周减轻机械性异常性疼痛。在原代星形胶质细胞的纯化培养物中，IgG免疫复合物（IgG-IC）增加了促炎细胞因子和趋化因子的转录。通过siRNA介导的Fcgr2a敲低，或通过抑制FcγRIIa效应器脾酪氨酸激酶（Syk）或核因子κB（NF-κB），可降低这些细胞因子和趋化因子的表达。这些数据表明，外周神经损伤后脊髓星形胶质细胞表达的FcγRIIa被激活，并可能通过释放促炎介质直接导致损伤诱导的触觉疼痛。这些发现扩展了我们对星形胶质细胞神经免疫信号如何促成机械性异常性疼痛发生的理解。观点：脊髓星形胶质细胞中FcγRIIa信号的激活促进神经损伤后的机械性异常性疼痛，并启动针对IgG免疫复合物的神经炎症途径。这些发现揭示了胶质细胞Fcγ受体处的自身抗体IgG信号作为缓解神经性疼痛的潜在治疗方法。
