Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Cell. 2019 Feb 7;176(4):716-728.e18. doi: 10.1016/j.cell.2018.12.022. Epub 2019 Jan 31.
Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.
感觉轴突在与细胞体分离后会发生退化，但外周神经的部分损伤可能会使受损轴突的完整性得以保留。我们发现，自然杀伤 (NK) 细胞受体 NKG2D 的内源性配体，即视黄酸早期 1（RAE1），在外周神经损伤后会在成年背根神经节神经元中重新表达，从而触发受损轴突的选择性退化。细胞毒性 NK 细胞通过渗出进入坐骨神经的浸润发生在挤压伤后 3 天内。通过基因细胞消融和细胞因子-抗体复合物刺激的组合，我们表明 NK 细胞功能与因损伤传入神经退化而导致的感觉丧失以及损伤后过敏发生率降低相关。这种 NK 细胞介导的损伤但完整感觉轴突选择性退化的神经免疫机制补充了瓦勒变性，并提示通过清除部分受损神经来调节 NK 细胞功能以解决疼痛性神经病的治疗潜力。
