A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation.
A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation.
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lincRNA-p21/miR-181 家族反馈环在系统性 LPS 和 MPTP 诱导的神经炎症过程中调节小胶质细胞的激活。
DOI：
10.1038/s41419-018-0821-5
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发表时间：
2018-07-23
影响因子：
9
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Ye Y;He X;Lu F;Mao H;Zhu Z;Yao L;Luo W;Sun X;Wang B;Qian C;Zhang Y;Lu G;Zhang S
小胶质细胞介导的持续神经炎症在帕金森病（PD）的发生和发展中的作用已经得到了很好的证实，但促进小胶质细胞激活的机制仍不清楚。lincRNA -p21是一种被广泛研究的长基因间非编码RNA (lincRNA)，在多种生物过程和疾病中起着关键作用。然而，其在小胶质细胞激活和炎症诱导的神经毒性中的作用尚未完全阐明。在这里，我们报道lincRNA-p21通过p53依赖的转录途径促进小胶质细胞的激活。我们进一步证明，lincRNA-p21与miR-181家族竞争性结合，并通过miR-181/PKC-δ途径诱导小胶质细胞活化。此外，PKC-δ诱导进一步增加p53/lincRNA-p21的表达，从而形成回路。综上所述，我们的研究结果表明，p53/lincRNA-p21与miR-181/PKC-δ形成了一个双负反馈回路，促进了持续的小胶质细胞激活和神经退行性疾病的恶化。
The role of microglial-mediated sustained neuroinflammation in the onset and progression of Parkinson’s disease (PD) is well established, but the mechanisms contributing to microglial activation remain unclear. LincRNA-p21, a well studied long intergenic noncoding RNA (lincRNA), plays pivotal roles in diverse biological processes and diseases. Its role in microglial activation and inflammation-induced neurotoxicity, however, has not yet been fully elucidated. Here, we report that lincRNA-p21 promotes microglial activation through a p53-dependent transcriptional pathway. We further demonstrate that lincRNA-p21 competitively binds to the miR-181 family and induces microglial activation through the miR-181/PKC-δ pathway. Moreover, PKC-δ induction further increases the expression of p53/lincRNA-p21 and thus forms a circuit. Taken together, our results suggest that p53/lincRNA-p21, together with miR-181/PKC-δ, form a double-negative feedback loop that facilitates sustained microglial activation and the deterioration of neurodegeneration.
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影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
影响因子：
4.8
作者：
Abbas, T;White, D;Bargonetti, J
通讯作者：
Bargonetti, J
影响因子：
4.8
作者：
Pierdomenico, Anna Maria;Recchiuti, Antonio;Romano, Mario
通讯作者：
Romano, Mario
影响因子：
16.6
作者：
Bu P;Wang L;Chen KY;Rakhilin N;Sun J;Closa A;Tung KL;King S;Kristine Varanko A;Xu Y;Huan Chen J;Zessin AS;Shealy J;Cummings B;Hsu D;Lipkin SM;Moreno V;Gümüş ZH;Shen X
通讯作者：
Shen X
影响因子：
5.8
作者：
Hulsmans, Maarten;Sinnaeve, Peter;Holvoet, Paul
通讯作者：
Holvoet, Paul