Inhibition of heat shock protein family A member 8 attenuates spinal cord ischemia-reperfusion injury via astrocyte NF-κB/NLRP3 inflammasome pathway HSPA8 inhibition protects spinal ischemia-reperfusion injury

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-kappa B) p65 phosphorylation, NLRP3 inflammasome-mediated caspase-1 activation, and subsequent interleukin (IL)-1 beta 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-kappa B, NLRP3, caspase-1, IL-1 beta, and IL-18. Further in vitro studies confirmed that HSPA8 knockdown protected astrocytes from OGD/R-induced injury via the blockade of NF-kappa B and NLRP3 inflammasome activation. Conclusion: Our findings indicate that knockdown of HSPA8 inhibits spinal astrocytic damage after SCII, which may provide a promising therapeutic strategy for SCII treatment.

Automated summary

The study showed that silencing HSPA8 can alleviate spinal cord damage caused by SCII by inhibiting astrocyte activation and NF-κB, NLRP3 inflammasome activation, leading to reduced neuroinflammation and protection of neurons.