Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

Cell & Bioscience

Hui Ren¹  Li Yang¹  Ying Bai¹  Ling Shen¹  Rongrong Huang¹  Zhongqiu Zhou¹  Ying Tang²  Mengchun Zhou³ 

[1] Department of Pharmacology, School of Medicine, Southeast University, 210009, Nanjing, Jiangsu, China;Department of Pharmacology, School of Medicine, Southeast University, 210009, Nanjing, Jiangsu, China;Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China;Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, Zhejiang, China;

关键词: Astrocyte;    Activation;    HECTD1;    LPS;    Neuroinflammation;   

DOI  :  10.1186/s13578-021-00572-x

来源: Springer

【 摘 要 】

BackgroundAstrocytes 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.ResultsHere, 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.ConclusionsOverall, 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.

【 授权许可】

CC BY