IRG1/itaconate increases IL-10 release to alleviate mechanical and thermal hypersensitivity in mice after nerve injury.
IRG1/itaconate increases IL-10 release to alleviate mechanical and thermal hypersensitivity in mice after nerve injury.
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IRG1/衣康酸增加 IL-10 释放以减轻神经损伤后小鼠的机械和热超敏反应
DOI：
10.3389/fimmu.2022.1012442
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发表时间：
2022
影响因子：
7.3
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Sun Q;Hu T;Zhang Y;Wang X;Liu J;Chen W;Wei C;Liu D;Wu W;Lan T;Ding Y;Luo Z;Liu M;Shen D;Xiao Z;Hu L;Pang M;Ma Y;Shi L;Wang P;Zhang J;Li Q;Yang F
炎症反应在神经病理性疼痛的发生、发展中起着重要作用。免疫应答基因1（IRG 1）在线粒体中脱羧生成衣康酸。衣康酸作为巨噬细胞的免疫调节剂，抑制感染性疾病中的炎症。最近，一项研究表明衣康酸衍生物抑制神经炎症并减轻小鼠的慢性疼痛。然而，内源性衣康酸在神经病理性疼痛中的作用及其分子机制尚未完全阐明。本研究采用质谱法检测神经损伤小鼠同侧脊髓中衣康酸的含量。建立Irg 1-/-小鼠模型，以确定内源性衣康酸在慢性压迫性神经损伤（CCI）模型中的作用。在雄性和雌性CCI小鼠中通过腹腔内和鞘内给药来评估外源性衣康酸盐的镇痛作用。脊髓应用4-OI也降低了CCI小鼠宽动态范围神经元的诱发反应。通过分子生物学实验探讨衣康酸酯潜在的镇痛机制，并在白细胞介素（IL）-10-/-小鼠中进行验证。结果发现CCI后脊髓中IRG 1和衣康酸水平显著升高，IRG 1缺乏加重了CCI小鼠的机械和热敏感性，而外源性给予衣康酸衍生物4-OI则减轻了CCI小鼠的神经病理性疼痛。在机制上，4-OI处理增加了IL-10水平，激活了脊髓中的STAT 3/β-内啡肽通路，并且在IL-10-/-小鼠中衣康酸的镇痛作用受到损害。最后，我们发现4-OI诱导的IL-10上调主要来自脊髓神经元，通过Nrf 2途径。本研究证实了内源性和外源性衣康酸盐在神经病理性疼痛模型中的镇痛作用，提示脊髓IL-10/STAT 3/β-内啡肽通路可能介导了衣康酸盐的镇痛作用。
Inflammation plays an important role in the occurrence and development of neuropathic pain. Immune-responsive gene 1 (IRG1) decarboxylatescis-aconitate to produce itaconate in the mitochondria. Itaconate serves as an immunomodulator of macrophages and represses inflammation in infectious diseases. Recently, a study showed that an itaconate derivative inhibits neuroinflammation and reduces chronic pain in mice. However, the function and molecular mechanisms of endogenous itaconate in neuropathic pain have not been fullyelucidated. In this study, the content of itaconate in the ipsilateral spinal cord after nerve-injured mice was detected with mass spectrometry. TheIrg1-/-mouse was constructed to determine the role of endogenous itaconate in the chronic constriction nerve injury (CCI) model. The analgesic effect of exogenous itaconate was assessed with intraperitoneal and intrathecal administration in both male and female CCI mice. The spinal application of 4-OI also reduced the evoked responses of wide dynamic range neurons in CCI mice. The potential analgesic mechanism of itaconate was explored through molecular biology experiments and verified in Interleukin(IL)-10-/-mice. We found the levels of itaconate and IRG1 in the spinal cord significantly increased after CCI.Irg1deficiency aggravated the mechanical and heat hypersensitivity, while the exogenous administration of the itaconate derivative 4-OI alleviated the neuropathic pain in male and female CCI mice. Mechanistically, the treatment of 4-OI increased the level of IL-10 and activates STAT3/β-endorphin pathway in the spinal cord, and the analgesia effect of itaconate was impaired inIL-10-/-mice. Finally, we showed that the upregulation of IL-10 induced by 4-OI was mainly from spinal neurons through Nrf2 pathway. This study demonstrated the analgesic effect of endogenous and exogenous itaconate in the neuropathic pain model, suggesting that the spinal IL-10/STAT3/β-endorphin pathway might mediate the analgesia effect of itaconate.
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