伤害性神经元通过MLKL许可的组蛋白释放抑制中性粒细胞胞外陷阱的形成
Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.
摘要(中文译文)
背根神经节（DRG）中涉及中性粒细胞的神经炎症在慢性疼痛中发挥双刃剑作用。DRG神经元与中性粒细胞之间的相互作用如何参与慢性疼痛的发生仍不清楚。在此，我们报道MLKL——坏死性凋亡的关键分子——在伤害性神经元细胞核中组成性表达，并与组蛋白H3结合。外周炎症破坏了MLKL/H3相互作用，导致MLKL向细胞质转位及组蛋白H3释放。细胞外组蛋白H3诱导神经元过度活跃、中性粒细胞胞外诱捕网（NET）形成及痛觉过敏，其机制可能通过P2X7受体和Toll样受体4介导。伤害性神经元特异性敲除Mlkl显著降低痛阈并加剧NET形成，且不依赖于细胞死亡。中和细胞外组蛋白、清除细胞外DNA或恢复MLKL的核定位，均可减少Mlkl小鼠的NET形成和痛觉过敏。这些数据表明，由MLKL-组蛋白-NET级联介导的伤害性神经元-中性粒细胞相互作用，可能成为慢性炎症性疼痛的潜在治疗靶点。
Abstract
Neutrophil-involved neuroinflammation in dorsal root ganglion (DRG) plays double-sword roles in chronic pain. How DRG neuron-neutrophil interaction contributes to chronic pain remains unclear. Here, we report that MLKL, a key molecule in necroptosis, is constitutively expressed in the nucleus of nociceptive neurons and binds to histone H3. Periphery inflammation disrupted MLKL/H3 interaction, leading to cytoplasmic translocation of MLKL and release of histone H3. Extracellular histone H3 induces neuronal hyperactivity, neutrophil extracellular trap (NET), and hyperalgesia, possibly through P2X7 receptor and Toll-like receptor 4. Nociceptive-specific depletion of Mlkl significantly decreased pain threshold and exacerbated NET formation independent of cell death. Neutralizing extracellular histone, clearing extracellular DNA or restoring nuclear localization of MLKL can reduce both NET formation and hyperalgesia in Mlklmice. These data demonstrated that the nociceptive neuron-neutrophil interaction mediated by this MLKL-histone-NET cascade may serve as a potential therapeutic target for chronic inflammatory pain.
如何引用
AMA
Han Meng, Wenchao Hu, Enming Kang, Qing Xu, Pengfei Wang, Xuyang Yi, et al. Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117457.
APA
Han Meng, Wenchao Hu, Enming Kang, Qing Xu, Pengfei Wang, Xuyang Yi, et al (2026). Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117457
GB/T 7714
Han Meng, Wenchao Hu, Enming Kang, Qing Xu, Pengfei Wang, Xuyang Yi, et al. Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117457.
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