Scavenger Receptor BI Protects against Septic Death through Its Role in Modulating Inflammatory Response

被引:90
作者
Guo, Ling
Song, Zhiqing
Li, Mengting
Wu, Qingan
Wang, Dan
Feng, Hong
Bernard, Philip
Daugherty, Alan [2 ]
Huang, Bin [3 ]
Li, Xiang-An [1 ]
机构
[1] Univ Kentucky, Sch Med, Dept Pediat, Lexington, KY 40536 USA
[2] Univ Kentucky, Sch Med, Dept Internal Med, Lexington, KY 40536 USA
[3] Univ Kentucky, Sch Med, Kentucky Canc Registry, Lexington, KY 40536 USA
基金
美国国家卫生研究院;
关键词
NITRIC-OXIDE SYNTHASE; DENSITY-LIPOPROTEIN BINDING; SR-BI; HDL RECEPTOR; REDUCES ATHEROSCLEROSIS; APOLIPOPROTEIN-E; PREMATURE DEATH; UNITED-STATES; LIVER-INJURY; MICE;
D O I
10.1074/jbc.M109.020933
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sepsis is a leading cause of death that is characterized by uncontrolled inflammatory response. In this study, we report that scavenger receptor BI (SR-BI), a high density lipoprotein receptor, is a critical survival factor of sepsis. We induced sepsis using an established septic animal model, cecal ligation and puncture (CLP). CLP induced 100% fatality in SR-BI-null mice but only 21% fatality in wild type littermates. SR-BI-null mice exhibited aberrant inflammatory responses with delayed inflammatory cytokine generation at the early stage of sepsis and highly elevated inflammatory cytokine production 20 h after CLP treatment. To understand the mechanisms underlying SR-BI protection, we elucidated the effect of macrophage SR-BI on inflammatory cytokine generation. Macrophages from SR-BI-null mice produced significantly higher levels of inflammatory cytokines than those of wild type controls in response to LPS. Importantly, transgenic mice overexpressing SR-BI were more resistant to CLP-induced septic death. Using an HEK-Blue (TM) cell system, we demonstrated that expression of SR-BI suppressed TLR4-mediated NF-kappa B activation. To understand why SR-BI-null mice had a delayed inflammatory response, we elucidated the effect of SR-BI on LPS clearance during sepsis. Compared with wild type controls, SR-BI-null mice had lower plasma LPS levels in the early stage of sepsis and elevated plasma LPS levels 20 h following CLP treatment. In conclusion, our findings demonstrate that SR-BI is a critical protective modulator of sepsis in mice. SR-BI exerts its protective function through its role in modulating inflammatory response in macrophages and facilitating LPS recruitment and clearance.
引用
收藏
页码:19826 / 19834
页数:9
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