Inhibition of heat shock protein family A member 8 attenuates spinal cord ischemia–reperfusion injury via astrocyte NF-κB/NLRP3 inflammasome pathway

Journal of Neuroinflammation

Zhiheng Ren¹  Wenfu Li¹  Rao Fu¹  Ce Xu²  Zhirong Huan²  Hao Yao²  Xin Ge³  Ying Tang⁴  Yang Yang⁵  Jingyi Mi⁶ 

[1] Department of Anatomy, School of Medicine, Sun Yat-Sen University, 510080, Guangzhou, Guangdong, China;Department of ICU, Wuxi 9Th Affiliated Hospital of Soochow University, 214000, Wuxi, Jiangsu, China;Department of ICU, Wuxi 9Th Affiliated Hospital of Soochow University, 214000, Wuxi, Jiangsu, China;Orthopedic Institution of Wuxi City, 214000, Wuxi, Jiangsu, China;Department of Microbiology, Biochemistry, & Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, 07103, Newark, NJ, USA;Brain Research Centre and Department of Biology, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China;Department of Neurosurgery, Central Hospital of Jinzhou, 121001, Jinzhou, Liaoning, China;Department of Sports Medicine, Wuxi 9Th Affiliated Hospital of Soochow University, 214000, Wuxi, Jiangsu, China;

关键词: HSPA8;    Spinal cord ischemia–reperfusion injury;    Astrocyte;    Neuroinflammation;    NF-κB;    NLRP3;   

DOI  :  10.1186/s12974-021-02220-0

来源: Springer

【 摘 要 】

BackgroundAstrocyte over-activation and extensive neuron loss are the main characteristic pathological features of spinal cord ischemia–reperfusion injury (SCII). Prior studies have placed substantial emphasis on the role of heat shock protein family A member 8 (HSPA8) on postischemic myocardial inflammation and cardiac dysfunction. However, it has never been determined whether HSPA8 participates in astrocyte activation and thus mediated neuroinflammation associated with SCII.MethodsThe left renal artery ligation-induced SCII rat models and oxygen–glucose deprivation and reoxygenation (OGD/R)-induced rat primary cultured astrocytes were established. The lentiviral vector encoding short hairpin RNA targeting HSPA8 was delivered to the spinal cord by intrathecal administration or to culture astrocytes. Then, the spinal neuron survival, gliosis, and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and its related pro-inflammatory cytokines were analyzed.ResultsSCII significantly enhanced the GFAP and HSPA8 expression in the spinal cord, resulting in blood–brain barrier breakdown and the dramatical loss of spinal neuron and motor function. Moreover, injury also increased spinal nuclear factor-kappa B (NF-κB) p65 phosphorylation, NLRP3 inflammasome-mediated caspase-1 activation, and subsequent interleukin (IL)-1β as well as IL-18 secretion. Silencing the HSPA8 expression efficiently ameliorated the spinal cord tissue damage and promoted motor function recovery after SCII, through blockade of the astrocyte activation and levels of phosphorylated NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Further in vitro studies confirmed that HSPA8 knockdown protected astrocytes from OGD/R-induced injury via the blockade of NF-κB and NLRP3 inflammasome activation.ConclusionOur findings indicate that knockdown of HSPA8 inhibits spinal astrocytic damage after SCII, which may provide a promising therapeutic strategy for SCII treatment.

【 授权许可】

CC BY