Involvement of Histone Lysine Crotonylation in the Regulation of Nerve-Injury-Induced Neuropathic Pain.
Involvement of Histone Lysine Crotonylation in the Regulation of Nerve-Injury-Induced Neuropathic Pain.
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组蛋白赖氨酸巴豆酰化参与神经损伤引起的神经病理性疼痛的调节
DOI：
10.3389/fimmu.2022.885685
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发表时间：
2022
影响因子：
7.3
通讯作者：
Jiang BC
中科院分区：
文献类型：
--
作者：
Zou Y;Bai XH;Kong LC;Xu FF;Ding TY;Zhang PF;Dong FL;Ling YJ;Jiang BC
组蛋白赖氨酸巴豆酰化（KCR）是一种新型的表观遗传修饰，在调节多种生物学过程和多种疾病中起着重要作用。然而，KCR是否参与神经病理性疼痛仍有待阐明。我们发现KCR发生在三叉神经节（TG）的巨噬细胞、感觉神经元和卫星胶质细胞、延髓的神经元、星形胶质细胞和小胶质细胞中。TG中的KCR主要在小型和中型感觉神经元中检测到，在较大的神经元中检测到较少程度。周围神经损伤后，三叉神经和背根神经节的巨噬细胞和延髓的小胶质细胞的KCR水平升高，但感觉神经元的KCR水平降低。通过TG内或鞘内给予C646抑制组蛋白巴豆酰转移酶（p300）可显著减轻部分眶下神经横断（pIONT）或脊神经结扎（SNL）诱导的机械异常性疼痛和热痛觉过敏。TG内或鞘内给予巴豆酰辅酶A三锂盐以上调KCR剂量依赖性诱导的小鼠机械异常性疼痛和热痛觉过敏。机制上，抑制p300减轻了pIONT诱导的巨噬细胞活化，并减少了疼痛相关炎性细胞因子TNFα、IL 1 β和趋化因子Ccl 2和Cxcl 10的表达。相应地，外源性巴豆酰辅酶A诱导TG中巨噬细胞活化和TNFα、IL 1 β、IL 6、Ccl2和Ccl7的表达，C646可抑制这些表达。这些发现表明，组蛋白巴豆酰化可能在功能上参与神经病理性疼痛和神经炎症调节。
Histone lysine crotonylation (KCR), a novel epigenetic modification, is important in regulating a broad spectrum of biological processes and various diseases. However, whether KCR is involved in neuropathic pain remains to be elucidated. We found KCR occurs in macrophages, sensory neurons, and satellite glial cells of trigeminal ganglia (TG), neurons, astrocytes, and microglia of the medulla oblongata. KCR in TG was detected mainly in small and medium sensory neurons, to a lesser extent in large neurons. Peripheral nerve injury elevated KCR levels in macrophages in the trigeminal and dorsal root ganglia and microglia in the medulla oblongata but reduced KCR levels in sensory neurons. Inhibition of histone crotonyltransferases (p300) by intra-TG or intrathecal administration of C646 significantly alleviated partial infraorbital nerve transection (pIONT)- or spinal nerve ligation (SNL)-induced mechanical allodynia and thermal hyperalgesia. Intra-TG or intrathecal administration of Crotonyl coenzyme A trilithium salt to upregulate KCR dose-dependently induced mechanical allodynia and thermal hyperalgesia in mice. Mechanismly, inhibition of p300 alleviated pIONT-induced macrophage activation and reduced the expression of pain-related inflammatory cytokines Tnfα, Il1β and chemokines Ccl2 and Cxcl10. Correspondingly, exogenous crotonyl-CoA induced macrophage activation and the expression of Tnfα, Il1β, Il6, Ccl2 and Ccl7 in TG, which C646 can repress. These findings suggest that histone crotonylation might be functionally involved in neuropathic pain and neuroinflammation regulation.
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DOI：
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发表时间：
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期刊：
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影响因子：
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