Brain Res. 2023 Jul 11. pii: S0006-8993(23)00253-6. [Epub ahead of print] 148482
Acute ischemic stroke (AIS) is known to trigger a cascade of inflammatory events that induces secondary tissue damages. As a type of regulated inflammatory cell death, necroptosis is associated with AIS, whilst its regulation during neuroinflammation is not well understood. In particular, the actual function of NOD-like-receptor family pyrin domain-containing-3(NLRP3) inflammasome in cortical neuronal necroptosis still not clear. Herein, we explored the function of nuclear factor erythroid-2 related factor-2 (Nrf2)/ heme oxygenase-1 (HO-1) in oxygen-glucose deprivation (OGD) induced neuronal necroptosis and its underlying mechanism. To establish an in vitro model of neuronal necrosis, we used OGD/caspase-8 inhibitors (Q-VD-OPh, QVD) to treat rat primary cortical neurons (PCNs) after reoxygenation, wherein we found that the model cause an elevated ROS levels by mediating TXNIP/NLRP3 interactions, which in turn activated the NLRP3 inflammasome. Also, we observed that regulation of nuclear factor erythroid-2 related factor-2 (Nrf2) promoted heme oxygenase-1 (HO-1) expression and decreased TXNIP (a protein that relate oxidative stress to activation of inflammasome) and ROS levels, which negatively regulated the expression of OGD-induced activation of NLRP3 inflammasomes. In addition, HO-1 weakened NLRP3 inflammation body activation, which suggests that Nrf2-regulated HO-1 could block the interaction between TXNIP and NLRP3 in OGD/R-treated cortical neurons by inhibiting ROS production. Our study has discovered the importance of Nrf2/HO-1 signaling cascade for inhibiting inflammasome of NLRP3, which negatively regulated necrosis. Therefore, NLRP3 is considered a potential target for a novel neuroprotective approach, which can expand the therapeutic windows of stroke drugs.
Keywords: NLRP3 inflammasome; Nrf2/HO-1; ROS; necroptosis; neuron