Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis.
Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis.
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HECTD1 通过 sigma-1R-JNK/p38-FOXJ2 轴参与 LPS 诱导的星形胶质细胞激活
DOI：
10.1186/s13578-021-00572-x
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发表时间：
2021-03-30
影响因子：
7.5
通讯作者：
Bai Y
中科院分区：
文献类型：
--
作者：
Tang Y;Zhou M;Huang R;Shen L;Yang L;Zhou Z;Ren H;Bai Y
星形胶质细胞参与哺乳动物中枢神经系统（CNS）的先天炎症反应。HECT结构域E3泛素蛋白连接酶1 （hecd1）在小胶质细胞激活过程中起作用，提示与神经炎症有关。然而，hector 1在星形胶质细胞中的潜在作用在很大程度上仍然未知。在这里，我们证明了100 ng/ml脂多糖（LPS）处理后，小鼠原代星形胶质细胞中hector 1上调。体外基因敲低或体内星形胶质细胞特异性敲低可抑制lps诱导的星形胶质细胞活化，而体外过表达hector 1可促进lps诱导的星形胶质细胞活化。在机制上，我们发现LPS激活了σ-1R-JNK/p38通路，而σ-1R拮抗剂BD1047、JNK抑制剂SP600125或p38抑制剂SB203580逆转了LPS诱导的hector 1表达，从而恢复了LPS诱导的星形胶质细胞活化。此外，FOXJ2还可作为一种转录因子，用BD1047、SB203580和SP600125预处理小鼠原代星形胶质细胞可显著抑制lps介导的FOXJ2向细胞核的易位。总之，我们目前的研究结果表明，hector 1通过激活σ-1R-JNK/p38-FOXJ2通路参与LPS诱导的星形胶质细胞活化，并为LPS诱导的神经炎症或任何其他神经炎症疾病提供了潜在的治疗策略。在线版本包含补充材料，可在10.1186/s13578-021-00572-x获得。
Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders. The online version contains supplementary material available at 10.1186/s13578-021-00572-x.
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