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

Abstract

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 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. Conclusion Our findings indicate that knockdown of HSPA8 inhibits spinal astrocytic damage after SCII, which may provide a promising therapeutic strategy for SCII treatment.

Long non-coding RNA H19 contributes to spinal cord ischemia/reperfusion injury through increasing neuronal pyroptosis by miR-181a-5p/HMGB1 axis

“…AIM2 inflammasome contributed to spinal cord injury by releasing cleaved caspase-1 and IL-1β [ 9 ]. The expression of HSPA8 was efficiently enhanced after SCI/R injury, which activated the NF-κB-NLRP3 inflammasome signaling, resulting in spinal ischemia-reperfusion injury [ 30 ]. In this study, we demonstrated that OGD/R treatment promoted PC12 cell pyroptosis and inflammation, while knockdown of H19 significantly reversed these results, indicating H19 protect PC12 cells from OGD/R [ 31 ].…”

NLRP3 Inflammasome Is Involved in Cocaine-Mediated Potentiation on Behavioral Changes in CX3CR1-Deficient Mice

“…Another limitation is that we focused on microglial NLRP3 only. Actually, NLRP3 inflammasome is also expressed in other brain cells including astrocytes [ 62 , 63 ], and astrocyte activation also contributes to the elevation of neuroinflammation levels. The astrocyte NLRP3 inflammasome might also participate in the potentiation of cocaine-mediated reward effects in CX3CR1 deficiency mice.…”

Insight Into the Mechanism of Exercise Preconditioning in Ischemic Stroke

“…They assist in clearing excessive potassium ions around neurons by regulating the osmotic balance of ions and water and maintaining the relative stability of the neuronal external environment ( Jensen et al, 2013 ; Dinuzzo et al, 2017 ; Yang et al, 2021b ). Astrocytes are also involved in the inflammatory response post cerebral ischemia ( Gao et al, 2021 ; Mi et al, 2021 ; Kieran et al, 2022 ), although their roles are different in different stages of inflammation. In the initial phase of inflammation, astrocytes behave as antigen-presenting cells and secrete pro-inflammatory antigen-presenting cytokines to protect tissues from damage.…”