Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin.
Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin.
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DOI：
10.1016/j.jconrel.2017.12.025
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发表时间：
2018-02-28
期刊：
影响因子：
--
通讯作者：
Muzykantov VR
中科院分区：
文献类型：
--
作者：
Shuvaev VV;Kiseleva RY;Arguiri E;Villa CH;Muro S;Christofidou-Solomidou M;Stan RV;Muzykantov VR
与toll样受体（TLR）结合的炎症介质诱导超氧阴离子在随后的内体中内流。在内皮细胞中，内体超氧化物过剩导致促炎激活，TLR4激动剂优先通过小泡源性内体起作用。为了验证SOD传递到小泡可能特异性抑制这一病理途径的假设，我们将SOD与体内特异性定位于内皮小泡的质乳囊泡相关蛋白（Plvap）的抗体（Ab/SOD，大小约10nm）结合，并比较其与非小泡靶CD31/PECAM-1的作用。Plvap Ab/SOD与内皮细胞结合的效率远低于CD31 Ab/SOD，但其阻断LPS信号传导的效率高于CD31 Ab/SOD。filipin破坏富含胆固醇的膜结构域可抑制Plvap Ab/SOD内吞作用和LPS信号传导，暗示在这两个过程中存在小泡依赖途径。针对Plvap和CD31的Ab/SOD偶联物在小鼠静脉注射后均在肺内积累，但前者对lps诱导的肺部炎症及血浆干扰素- β、- γ和白细胞介素-27水平升高的抑制作用更深刻。综上所述，这些结果表明，将SOD靶向递送到特定的细胞室可能提供有效的、机械上精确的阻断由活性氧介导的促炎信号。
Inflammatory mediators binding to Toll-Like receptors (TLR) induce an influx of superoxide anion in the ensuing endosomes. In endothelial cells, endosomal surplus of superoxide causes pro-inflammatory activation and TLR4 agonists act preferentially via caveolae-derived endosomes. To test the hypothesis that SOD delivery to caveolae may specifically inhibit this pathological pathway, we conjugated SOD with antibodies (Ab/SOD, size ~10nm) to plasmalemmal vesicle-associated protein (Plvap) that is specifically localized to endothelial caveolae in vivo and compared its effects to non-caveolar target CD31/PECAM-1. Plvap Ab/SOD bound to endothelial cells in culture with much lower efficacy than CD31 Ab/SOD, yet blocked the effects of LPS signaling with higher efficiency than CD31 Ab/SOD. Disruption of cholesterol-rich membrane domains by filipin inhibits Plvap Ab/SOD endocytosis and LPS signaling, implicating the caveolae-dependent pathway(s) in both processes. Both Ab/SOD conjugates targeted to Plvap and CD31 accumulated in the lungs after IV injection in mice, but the former more profoundly inhibited LPS-induced pulmonary inflammation and elevation of plasma level of interferon-beta and -gamma and interleukin-27. Taken together, these results indicate that targeted delivery of SOD to specific cellular compartments may offer effective, mechanistically precise interception of pro-inflammatory signaling mediated by reactive oxygen species.
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影响因子：
3.4
作者：
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通讯作者：
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影响因子：
4.4
作者：
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影响因子：
4.8
作者：
Guillot, L;Medjane, S;Si-Tahar, M
通讯作者：
Si-Tahar, M
影响因子：
10.8
作者：
Kowalski, Piotr S.;Zwiers, Peter J.;Kamps, Jan A. A. M.
通讯作者：
Kamps, Jan A. A. M.
用于血管输送抗炎剂的纳米载体。
DOI：
10.1146/annurev-pharmtox-011613-140002
发表时间：
2014
影响因子：
12.5
作者：
Howard MD;Hood ED;Zern B;Shuvaev VV;Grosser T;Muzykantov VR
通讯作者：
Muzykantov VR