Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury.
Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury.
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将白细胞介素 22 与载脂蛋白 A-I 结合可改善小鼠对乙酰氨基酚引起的肝损伤
作者：
Chen W;Zhang X;Fan J;Zai W;Luan J;Li Y;Wang S;Chen Q;Wang Y;Liang Y;Ju D
越来越多的证据表明，白细胞介素-22（IL-22）在预防肝损伤方面具有巨大的潜力，但其多效性和在致癌、类风湿性关节炎和银屑病中的致病作用限制了其全身应用。在这里，我们首先开发了一种纳米颗粒（脂质体IA）作为肝靶向药物，通过IL-22拴系到载脂蛋白A-I（ApoA-I）的基因治疗载体。脂质体IA采用薄膜分散法制备，复合物具有理想的纳米颗粒尺寸，良好的多分散指数，高效转染，以及优异的血清和储存稳定性。生物分布和肝脏STAT 3磷酸化研究表明，IL-22与ApoA-I连接导致高效的肝脏靶向。更重要的是，我们的研究表明，单剂量的脂质体IA能够保护小鼠免受对乙酰氨基酚诱导的肝损伤，并且不会引发体内炎症反应或全身毒性。在此过程中，观察到激活的STAT 3/Erk和Akt/mTOR信号转导，以及抑制活性氧（ROS）的产生，从而防止线粒体功能障碍。这些研究表明，IL-22拴系到载脂蛋白A-I可以靶向和改善对乙酰氨基酚诱导的急性肝损伤，这突出了IL-22递送的靶向策略可能具有广泛的实用性，用于保护肝细胞损伤。
Increasing evidence indicates that interleukin-22 (IL-22) holds tremendous potential as a protective agent in preventing liver injury, but its pleiotropic effects and pathogenic role in carcinogenesis, rheumatoid arthritis and psoriasis restrict its systemic application. Here, we first developed a nanoparticle (liposIA) as a liver-targeted agent through IL-22 tethered to apolipoprotein A-I (ApoA-I) in a gene therapy vector. LiposIA was prepared using thin film dispersion method and the complexes exhibited desirable nanoparticle size, fine polydisperse index, highly efficient transfection, and excellent serum and storage stability. Biodistribution and hepatic STAT3 phosphorylation studies revealed that IL-22 tethered to ApoA-I led to highly efficient liver targeting. More importantly, our studies showed that a single-dose of liposIA was able to protect mice against acetaminophen-induced liver injury and did not initiate inflammatory response or systemic toxicity in vivo. During this process, activated STAT3/Erk and Akt/mTOR signaling transductions were observed, as well as inhibition of reactive oxygen species (ROS) generation, which prevented mitochondrial dysfunction. These studies demonstrated that IL-22 tethered to apolipoprotein A-I could target and ameliorate acetaminophen-induced acute liver injury, which highlighted that a targeted strategy for IL-22 delivery might have broad utility for the protection of hepatocellular damage.
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