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

作者：Jingyi Mi, Yang Yang, Hao Yao, Zhirong Huan, Ce Xu, Zhiheng Ren, Wenfu Li, Ying Tang, Rao Fu, Xin Ge · 发表于：Journal of Neuroinflammation · 年份：2021 · DOI：10.1186/s12974-021-02220-0 · 被引用次数：54 · 研究领域：Inflammasome and immune disorders、Heat shock proteins research、Spinal Cord Injury Research

BACKGROUND: Astrocyte 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. METHODS: The 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. RESULTS: SCII 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 recov...