NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder.
NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder.
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中枢神经系统(CNS)的许多疾病，包括酒精使用障碍(AUD)，都与促炎性神经免疫信号的诱导和神经变性有关。在以前的研究中，我们发现Toll样受体(Toll-like Receptor，TLR)、活化的核因子-受体B p65(NF-κB p65，RERA)和其他促炎信号分子的表达增加。促炎性NADPH氧化酶产生与神经变性有关的活性氧物种。我们验证了AUD增加RELA激活增加NADPH氧化应激和内质网(ER)应激细胞死亡与人眶前皮质(OFC)神经细胞死亡相关的假设。在AUD OFC中，我们报道了几种NADPH氧化酶，双重氧化酶DUOX2，氧化应激脂质过氧化标记物4-HNE和DNA氧化标记物8-OHdG的基因诱导，它们与促炎性NF-κB激活的标志物RelA相关。伴随而来的是内质网应激相关调节蛋白葡萄糖调节蛋白78(GRP78)、跨膜感应器激活转录因子6(ATF6)、蛋白激酶类RNA内质网激酶(PERK)、肌醇需求激酶/核酸内切酶1(PIRE1)和促凋亡转录因子C/EBP同源蛋白(CHOP)的表达增加。NADPH氧化应激标志物的表达与内质网应激相关分子相关。氧化应激和内质网应激信号通路的诱导与细胞死亡相关半胱氨酸天冬氨酸酶的表达和神经细胞丢失相关。这些数据支持这一假说，即促炎相关性介导的NADPH氧化酶-氧化应激和内质网应激相关的信号级联反应与AUD患者死后OFC的神经细胞死亡有关。酒精使用障碍诱导人类眼眶前额叶皮质中的促炎性氧化酶，与促炎相关蛋白上调有关，这与参与氧化应激的NF-κB神经免疫信号一致。氧化应激的诱导与内质网(ER)应激相关的信号级联反应、细胞死亡相关的半胱氨酸酶的激活和神经元的丢失有关。这些数据表明，神经免疫信号和氧化应激在内质网应激诱导中是导致AUD患者OFC神经元死亡的原因。
Many disorders of the central nervous system (CNS), including alcohol use disorder (AUD), are associated with induction of proinflammatory neuroimmune signalling and neurodegeneration. In previous studies, we found increased expression of Toll‐like receptors (TLRs), activated NF‐κB p65 (RELA), and other proinflammatory signalling molecules. Proinflammatory NADPH oxidases generate reactive oxygen species, which are linked to neurodegeneration. We tested the hypothesis that AUD increased RELA activation increases NADPH oxidase‐oxidative stress and endoplasmic reticulum (ER) stress cell death cascades in association with neuronal cell death in the human orbitofrontal cortex (OFC). In the AUD OFC, we report mRNA induction of several NADPH oxidases, the dual oxidase DUOX2, and the oxidative stress lipid peroxidation marker 4‐HNE and the DNA oxidation marker 8‐OHdG that correlate with RELA, a marker of proinflammatory NF‐κB activation. This was accompanied by increased expression of the ER stress‐associated regulator protein glucose‐regulated protein 78 (GRP78), transmembrane sensors activating transcription factor 6 (ATF6), protein kinase RNA‐like endoplasmic reticulum kinase (PERK), and inositol‐requiring kinase/endonuclease 1 (pIRE1), and the pro‐apoptotic transcription factor C/EBP homologous protein (CHOP). Expression of NADPH oxidase‐oxidative stress markers correlate with ER stress‐associated molecules. Induction of oxidative stress and ER stress signalling pathways correlate with expression of cell death‐associated caspases and neuronal cell loss. These data support the hypothesis that proinflammatory RELA‐mediated induction of NADPH oxidase‐oxidative stress and ER stress‐associated signalling cascades is associated with neuronal cell death in the post‐mortem human OFC of individuals with AUD. Alcohol use disorder (AUD) induces proinflammatory oxidases in the human orbitofrontal cortex (OFC) in association with upregulation of proinflammatory RELA, consistent with NF‐κB neuroimmune signaling contributing to oxidative stress. Induction of oxidative stress is correlated with induction of endoplasmic reticulum (ER) stress‐associated signaling cascades and activation of cell death‐associated caspases and neuronal loss. These data implicate neuroimmune signaling and oxidative stress in induction of ER stress as contributing to neuronal death in the OFC of individuals with AUD.
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