Cationic nanocarriers induce cell necrosis through impairment of Na+/K+-ATPase and cause subsequent inflammatory response
| Autor: | Zhirong Zhang, Zhiyong Qian, Xiawei Wei, Yaxiong Sang, Xun Sun, Chengyu Jiang, Shun-Tao Luo, Yinglan Zhao, Senyi Deng, Hongxing Deng, Tinghong Ye, Jiong Li, Bin Shao, Zhiyao He, Shengyong Yang, Jiahuai Han, Hanshuo Yang, Shuang Zhang, Xiao Liang, Changyang Gong, Wei Wang, Min Wu, Li Yang, Maling Gou, Min Luo, Chengjian Zhao |
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| Rok vydání: | 2015 |
| Předmět: |
Programmed cell death
Necrosis Apoptosis Pharmacology Biology DNA Mitochondrial Ouabain necrosis Mice Cations Cell Line Tumor medicine Animals Humans Polyethyleneimine Cationic liposome Na+/K+-ATPase damage-associated molecular patterns Molecular Biology Inflammation Mice Knockout Chitosan Drug Carriers Cell Biology Mitochondria Nanostructures cationic nanocarriers Mice Inbred C57BL Toll-Like Receptor 9 Liposomes Myeloid Differentiation Factor 88 Biophysics Original Article Sodium-Potassium-Exchanging ATPase medicine.symptom Nanocarriers Intracellular Signal Transduction medicine.drug |
| Zdroj: | Cell Research |
| ISSN: | 1748-7838 1001-0602 |
| DOI: | 10.1038/cr.2015.9 |
| Popis: | Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical applications. 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. |
| Databáze: | OpenAIRE |
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