Cationic nanocarriers induce cell necrosis through impairment of Na^＋/K^＋-ATPase and cause subsequent inflammatory response  

作　　者：Xiawei Wei Bin Shao Zhiyao He Tinghong Ye Min Luo Yaxiong Sang Xiao Liang Wei Wang Shuntao Luo Shengyong Yang Shuang Zhang Changyang Gong Maling Gou Hongxing Deng Yinglan Zhao Hanshuo Yang Senyi Deng Chengjian Zhao Li Yang Zhiyong Qian Jiong Li Xun Sun Jiahuai Han Chengyu Jiang Min Wu Zhirong Zhang 

机构地区：[1]Key Laboratory of Drug Targeting of Ministry of Education, State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, China [2]State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China [3]State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry and Molecular Biology, Pelting Union Medical College, Beo'ing 100005, China [4]Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA

出　　处：《Cell Research》2015年第2期237-253,共17页细胞研究（英文版）

基　　金：Acknowledgments This work was funded by the National Natural Science Foundation of China （81123003） and the National Basic Research Program of China （2010CB529900）. We also thank Dr Kang Zhang （University of California, San Diego） for helpful discussions.

摘　　要：Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical appli- cations. The mechanism underlying their toxicity, such as the induction of inflammatory response, remains largely unknown. In the present study we found that injection of cationic nanocarriers, including cationic liposomes, PEI, and chitosan, led to the rapid appearance of necrotic cells. Cell necrosis induced by cationic nanocarriers is dependent on their positive surface charges, but does not require RIP1 and Mlkl. Instead, intracellular Na^＋ overload was found to accompany the cell death. Depletion of Na^＋ in culture medium or pretreatment of cells with the Na^＋/K^＋- ATPase cation-binding site inhibitor ouabain, protected cells from cell necrosis. Moreover, treatment with cationic nanocarriers inhibited Na^＋/K^＋-ATPase activity both in vitro and in vivo. The computational simulation showed that cationic carriers could interact with cation-binding site of Na^＋/K^＋-ATPase. Mice pretreated with a small dose of ouabain showed improved survival after injection of a lethal dose of cationic nanocarriers. Further analyses suggest that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA could trigger severe inflammation in vivo, which is mediated by a pathway involving TLR9 and MyD88 signaling. Taken together, our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na^＋/K^＋-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. Our study has important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.

关 键 词：cationic nanocarriers NECROSIS Na^＋/K^＋-ATPase inflammation damage-associated molecular patterns 

分 类 号：Q78[生物学—分子生物学] TB383[一般工业技术—材料科学与工程]