Lipoxin A4 Inhibits NLRP3 Inflammasome Activation in Rats With Non-compressive Disc Herniation Through the JNK1/Beclin-1/PI3KC3 Pathway.
Lipoxin A4 Inhibits NLRP3 Inflammasome Activation in Rats With Non-compressive Disc Herniation Through the JNK1/Beclin-1/PI3KC3 Pathway.
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脂氧素 A4 通过 JNK1/Beclin-1/PI3KC3 通路抑制非压缩性椎间盘突出大鼠 NLRP3 炎症小体激活
DOI：
10.3389/fnins.2020.00799
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发表时间：
2020
影响因子：
4.3
通讯作者：
Sun T
中科院分区：
文献类型：
--
作者：
Jin J;Xie Y;Shi C;Ma J;Wang Y;Qiao L;Li K;Sun T
非压缩性椎间盘突出症是由髓核组织和神经根的炎症反应引起的。脂毒素（Lipoxins, LXs）是体内重要的内源性抗炎介质，有助于抑制中性粒细胞募集和刺激单核细胞和巨噬细胞的自噬。在这里，我们研究了外源性脂肪素对非压缩性椎间盘突出大鼠影响的分子机制。建立大鼠非压缩性椎间盘突出模型。50只大鼠随机分为：假手术组、模型组、PI3K抑制剂（LY294002）组、脂素A4组（LXA4）、PI3K抑制剂和脂素A4组（LY294002 + LXA4）。大鼠脊髓神经元也建立了类似的分组。在不同时间监测机械痛阈和热痛阈的变化。ELISA检测促炎和抗炎介质的表达，免疫组化检测NLRP3和p-JNK1的表达水平。western blot检测自噬相关蛋白的表达水平。在体内，与假手术组相比，模型组各时间点疼痛阈值均明显降低。LY294002治疗进一步降低疼痛阈值。注射LXA4后，痛阈值明显升高，LY294002的作用明显减弱（p < 0.05）。非压缩性椎间盘突出大鼠的促炎细胞因子水平升高，LY294002治疗后促炎细胞因子水平进一步升高（p < 0.05）。而LXA4治疗可显著降低模型组上述促炎因子水平（p < 0.05）。抗炎介质的作用正好相反。与假手术组比较，模型组NLRP3表达明显升高（p < 0.05）。LY294002也增加了NLRP3的表达水平，而LXA4则产生相反的效果。western blot分析显示，模型组小鼠自噬相关蛋白表达显著降低，而LXA4组小鼠自噬相关蛋白表达显著升高（p < 0.05）。体外实验结果与体内实验结果一致。这些数据表明，LXA4通过调节JNK1/beclin-1/PI3KC3通路抑制非压缩性椎间盘突出大鼠NLRP3的激活。
Non-compressive disc herniation is induced by an inflammatory response from the nucleus pulposus tissue and nerve roots. Lipoxins (LXs) are important endogenous anti-inflammatory mediators in the body, helping to inhibit neutrophil recruitment and stimulate autophagy in monocytes and macrophages. Here, we investigated the molecular mechanisms underlying the effects of exogenous lipoxin administration on rats with non-compressive disc herniation. A non-compressive disc herniation model was established in rats. Fifty rats were randomly divided into: sham group, model group, PI3K inhibitor (LY294002) group, lipoxin A4 group (LXA4), and PI3K inhibitor and lipoxin A4 group (LY294002 + LXA4). Similar groupings were established for rat spinal neurons. Changes in the mechanical pain threshold and thermal pain threshold were monitored at different times. The expression of proinflammatory and anti-inflammatory mediators was assessed by ELISA, while immunohistochemistry was employed to measure the expression levels of NLRP3 and p-JNK1. The expression levels of autophagy-related proteins were measured by western blot. In vivo, the pain threshold was markedly decreased in the model group at each time point examined compared with that in sham group. LY294002 treatment further reduced the pain threshold. After LXA4 injection, the pain threshold was significantly increased, and the effect of LY294002 was significantly weakened (p < 0.05). The levels of proinflammatory cytokines were increased in rats with non-compressive disc herniation, and these levels were further increased by LY294002 treatment (p < 0.05). However, treatment with LXA4 significantly reduced the levels of these proinflammatory cytokines in the model group (p < 0.05). The opposite effect was observed for anti-inflammatory mediators. The expression of NLRP3 was largely increased in the model group compared with that in the sham group (p < 0.05). Treatment with LY294002 also increased the NLRP3 expression level, while the administration of LXA4 elicited the opposite effect. Furthermore, western blot analysis showed that the expression of autophagy-related proteins was greatly decreased in the model group, whereas it was significantly increased in the LXA4 group (p < 0.05). The in vitro results were consistent with the outcomes observed in vivo. These data suggested that LXA4 inhibited NLRP3 activation in rats with non-compressive disc herniation by regulating the JNK1/beclin-1/PI3KC3 pathway.
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DOI：
10.4049/jimmunol.1500936
发表时间：
2015-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Roach KM;Feghali-Bostwick CA;Amrani Y;Bradding P
通讯作者：
Bradding P
影响因子：
64.8
作者：
Fimia, Gian Maria;Stoykova, Anastassia;Cecconi, Francesco
通讯作者：
Cecconi, Francesco
影响因子：
8.8
作者：
Liu, Zhi-hua;Miao, Gui-shen;Sun, Tao
通讯作者：
Sun, Tao
在非压迫性腰椎间盘突出症大鼠模型中，脂氧素 A4 可能通过抑制脊髓 ERK、JNK 和 NF-κB/p65 和细胞因子信号（但不是 p38）来减轻神经根痛
影响因子：
3.3
作者：
Miao, G. -S;Liu, Z. -H;Sun, T.
通讯作者：
Sun, T.
影响因子：
8.3
作者：
Jia, Yanqiu;Jin, Wei;Lv, Peiyuan
通讯作者：
Lv, Peiyuan