Downregulated XBP-1 Rescues Cerebral Ischemia/Reperfusion Injury-Induced Pyroptosis via the NLRP3/Caspase-1/GSDMD Axis

by Selleckchem | Aug 08 2023

Ischemic stroke is a major condition that remains extremely problematic to treat. A cerebral reperfusion injury becomes apparent after an ischemic accident when reoxygenation of the afflicted area produces pathological side effects that are different than those induced by the initial oxygen and nutrient deprivation insult. Pyroptosis is a form of lytic programmed cell death that is distinct from apoptosis, which is initiated by inflammasomes and depends on the activation of Caspase-1. Then, Caspase-1 mobilizes the N-domain of gasdermin D (GSDMD), resulting in the release of cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). X-box binding protein l (XBP-1) is activated under endoplasmic reticulum (ER) stress to form an important transcription factor XBP-1 splicing (XBP-1s). The cerebral ischemia/reperfusion (CI/R) causes cytotoxicity, which correlates with the activation of splicing XBP-1 mRNA and NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasomes, along with increases in the expression and secretion of proinflammatory cytokines and upregulation of pyroptosis-related genes in HT22 cells and in the middle cerebral artery occlusion (MCAO) rat model. However, whether XBP-1 plays a role in regulating pyroptosis involved in CI/R is still unknown. Our present study showed that behavior deficits, cerebral ischemic lesions, and neuronal death resulted from CI/R. CI/R increased the mRNA level of XBP-1s, NLRP3, IL-1β, and IL-18 and the expressions of XBP-1s, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18. We further repeated this process in HT22 cells and C8-B4 cells and found that OGD/R decreased cell viability and increased LDH release, XBP-1s, NLRP3, Caspase-1, GSDMD-N, IL-1β, IL-18, and especially the ratio of pyroptosis, which were reversed by Z-YVAD-FMK and downregulated XBP-1. Our results suggest that downregulated XBP-1 inhibited pyroptosis through the classical NLRP3/Caspase-1/GSDMD pathway to protect the neurons.

Comments:

The passage you provided discusses the role of X-box binding protein 1 (XBP-1) in regulating pyroptosis in the context of cerebral ischemia/reperfusion (CI/R) injury. Let's break down the information:

Ischemic stroke is a condition caused by a lack of blood flow to the brain, leading to oxygen and nutrient deprivation. When reperfusion (reoxygenation) occurs after the initial ischemic event, it can result in a cerebral reperfusion injury, which has different pathological effects compared to the initial insult.

Pyroptosis is a type of programmed cell death that is distinct from apoptosis. It is initiated by inflammasomes and involves the activation of Caspase-1. Caspase-1 then triggers the release of cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). In the case of CI/R, pyroptosis-related genes are upregulated, and there is an increase in the expression and secretion of proinflammatory cytokines.

XBP-1 is a transcription factor that is activated under endoplasmic reticulum (ER) stress. It undergoes splicing to form XBP-1s, which is the active form of the protein. The passage suggests that XBP-1 may play a role in regulating pyroptosis in the context of CI/R, but it states that the exact role is still unknown.

The study mentioned in the passage investigated the effects of CI/R on behavior, cerebral ischemic lesions, and neuronal death. It found that CI/R increased the levels of XBP-1s, NLRP3 (a protein associated with inflammasome activation), IL-1β, IL-18, as well as the expression of various pyroptosis-related proteins such as Caspase-1 and gasdermin D (GSDMD). These findings were observed in both a rat model of middle cerebral artery occlusion (MCAO) and HT22 and C8-B4 cell lines.

In HT22 and C8-B4 cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R), which mimics the conditions of CI/R, the study found that downregulating XBP-1 resulted in decreased pyroptosis, as indicated by decreased expression of pyroptosis-related proteins and a reduction in the ratio of pyroptosis. This suggests that downregulation of XBP-1 inhibited pyroptosis through the NLRP3/Caspase-1/GSDMD pathway, potentially offering neuroprotection.

In summary, the study suggests that XBP-1 may play a role in regulating pyroptosis in the context of CI/R injury. Downregulating XBP-1 appeared to inhibit pyroptosis and protect neurons, potentially through the classical NLRP3/Caspase-1/GSDMD pathway. However, further research is needed to fully understand the mechanisms and potential therapeutic implications of these findings.