Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin

JOURNAL OF CONTROLLED RELEASE

卷:272

Article

Shuvaev, Vladimir V.¹  Kiseleva, Raisa Yu.¹  Arguiri, Evguenia²  Villa, Carlos H.¹  Muro, Silvia³  Christofidou-Solomidou, Melpo²  Stan, Radu V.⁴  Muzykantov, Vladimir R.¹ 

[1] Univ Penn, Dept Pharmacol, Ctr Translat Targeted Therapeut, Nanomed,Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Med, Allergy & Crit Care Div, Philadelphia, PA 19104 USA

[3] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA

[4] Geisel Sch Med Dartmouth, Dept Biochem & Cell Biol, Lebanon, NH USA

关键词: Intracellular delivery;    Endothelial cells;    Vascular immunotargeting;    Plasmalemmal vesicle-associated protein;    Caveolae;   

DOI  :  10.1016/j.jconrel.2017.12.025

来源: Elsevier

【 摘 要 】

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 similar to 10 nm) 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.

【 授权许可】

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