Novel role of inflammasome activation in ART neurotoxicity

摘要 抗逆转录病毒药物的毒性与HIV感染者的脑病理和认知功能减退有关 然而，这些机制还没有完全被理解。抗逆转录病毒药物毒性的重要性 通过在艾滋病毒中引入暴露前预防措施(PrEP)而得到进一步加强 预防。血脑屏障(BBB)处于接触抗逆转录病毒药物的第一线， 使脑内皮细胞在ART毒性研究中特别相关。而当 抗逆转录病毒药物通常只能在脑实质中达到亚治疗水平，他们的药物 血浆浓度足以对脑血管系统产生负面影响，使大脑 血管内皮细胞是中枢神经系统ART毒性的主要靶点。当前的应用程序基于我们的 令人兴奋的发现表明，暴露于ART会导致线粒体功能障碍和改变 神经前体细胞(NPC)的神经发生。线粒体失调是一个很强的诱因 事实上，我们的结果暗示ART诱导的炎症体激活。 脑血管毒性。从机制上讲，拟议的工作集中在一种新的途径上 脑内皮细胞与血管周围神经前体细胞间的激活通讯 炎症性小体。中心假设是ART激活了大脑中的炎症体。 血管内皮细胞，随后释放白细胞介素1β，然后影响成人的神经发生 神经前体细胞，减少其向成熟神经元的分化，并有助于认知 拒绝。在整个提案中，我们将区分高CNS的ART的影响 穿透效率(CPE)与低CPE的ART相比。我们的应用程序提供了一个独特的、机械的、 以及对ART诱导的毒性和神经炎症的翻译视角 认知障碍。拟议研究的完成有望建立新的 抗ART毒性的治疗靶点。

ABSTRACT Toxicity of ART contributes to brain pathology and cognitive decline observed in HIV-infected individuals; however, the mechanisms are not fully understood. The importance of ART toxicity has been further enhanced by the introduction of pre-exposure prophylaxis (PrEP) into HIV prevention. The blood-brain barrier (BBB) is on the first line of exposure to antiretroviral drugs, making the brain endothelium particularly relevant in studies on toxicity of ART. While antiretroviral drugs frequently achieve only sub-therapeutic levels in the brain parenchyma, their plasma concertations are sufficient to negatively impact the brain vasculature, making the brain endothelium the main target of ART toxicity in the CNS. The current application is based on our exciting findings indicating that ART exposure results in mitochondrial dysfunction and alterations of neurogenesis of neural progenitor cells (NPCs). Mitochondrial dysregulation is a strong inducer of inflammasome, and indeed, our results implicate inflammasome activation in ART-induced cerebral vascular toxicity. Mechanistically, the proposed work is focused on a novel pathway of intercellular communication between the brain endothelium and perivascular NPCs via activation of inflammasome. The central hypothesis is that ART activates inflammasome in brain endothelial cells, followed by release of IL1β, which then affects adult neurogenesis of NPCs, diminishing their differentiation into mature neurons and contributing to cognitive decline. Throughout the proposal, we will differentiate the impact of ART with high CNS penetrating efficacy (CPE) vs. ART with low CPE. Our application offers a unique, mechanistic, and translational perspective on ART-induced toxicity and neuroinflammation that results in cognitive impairment. The completion of the proposed study promises to establish new therapeutic targets to protect against toxicity of ART.