Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90033, USA.
Department of Neurology, Keck School of Medicine, HCT 1520 San Pablo St, Los Angeles, CA, 90033, USA.
J Neuroimmune Pharmacol. 2019 Jun;14(2):263-277. doi: 10.1007/s11481-018-9816-3. Epub 2018 Oct 23.
Chronic low-grade neuroinflammation is increasingly implicated in organ damage caused by alcohol abuse. Purinergic P2X7 receptors (P2X7Rs) play an important role in the generation of inflammatory responses during a number of CNS pathologies as evidenced from studies using pharmacological inhibition approach. P2X7Rs antagonism has not been tested during chronic alcohol abuse. In the present study, we tested the potential of P2X7R antagonist A804598 to reduce/abolish alcohol-induced neuroinflammation using chronic intragastric ethanol infusion and high-fat diet (Hybrid) in C57BL/6J mice. We have previously demonstrated an increase in neuroinflammatory response in 8 weeks of Hybrid paradigm. In the present study, we found neuroinflammatory response to 4 weeks of Hybrid exposure. A804598 treatment reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of number of inflammatory markers, including IL-1β, iNOS, CXCR2, and components of inflammatory signaling pathways, such as TLR2, CASP1, NF-kB1 and CREB1, as well in the protein levels of pro-IL-1β and Nf-kB1. The P2X7R antagonist did not affect the increase in mRNA levels of fraktalkine (CX3CL1) and its receptor CX3CR1, an interaction that plays a neuroprotective role in neuron-glia communication. P2X7R antagonism also resulted in reduction of the inflammatory markers but did not alter steatosis in the liver. Taken together, these findings demonstrate how P2X7R antagonism suppresses inflammatory response in brain and liver but does not alter the neuroprotective response caused by Hybrid exposure. Overall, these findings support an important role of P2X7Rs in inflammation in brain and liver caused by combined chronic alcohol and high-fat diet. Graphical Abstract ᅟ.
慢性低度神经炎症与酒精滥用引起的器官损伤关系日益密切。嘌呤能 P2X7 受体（P2X7Rs）在许多中枢神经系统疾病的炎症反应产生中发挥重要作用，这一点已被药理学抑制方法的研究证实。在慢性酒精滥用期间，尚未对 P2X7R 拮抗剂进行测试。在本研究中，我们使用慢性胃内乙醇输注和高脂肪饮食（Hybrid）在 C57BL/6J 小鼠中测试了 P2X7R 拮抗剂 A804598 减少/消除酒精引起的神经炎症的潜力。我们之前已经证明，在 8 周的 Hybrid 模型中，神经炎症反应增加。在本研究中，我们发现 Hybrid 暴露 4 周后会引起神经炎症反应。A804598 治疗逆转了小胶质细胞和星形胶质细胞的变化，减少/消除了许多炎症标志物的 mRNA 水平的增加，包括 IL-1β、iNOS、CXCR2 和炎症信号通路的组成部分，如 TLR2、CASP1、NF-kB1 和 CREB1，以及前 IL-1β和 Nf-kB1 的蛋白水平。该 P2X7R 拮抗剂不影响 fraktalkine（CX3CL1）及其受体 CX3CR1 的 mRNA 水平的增加，这种相互作用在神经元-胶质细胞通讯中发挥神经保护作用。P2X7R 拮抗剂也导致炎症标志物减少，但不改变肝脏中的脂肪变性。总之，这些发现表明 P2X7R 拮抗如何抑制大脑和肝脏中的炎症反应，但不改变 Hybrid 暴露引起的神经保护反应。总体而言，这些发现支持 P2X7Rs 在慢性酒精和高脂肪饮食联合引起的大脑和肝脏炎症中的重要作用。
