Scavenger Receptor BI Protects against Septic Death through Its Role in Modulating Inflammatory Response.
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-kappaB 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.
Guo
Ling
L
Department of Pediatrics, University of Kentucky Medical School, Lexington, Kentucky 40536, USA.
Song
Zhiqing
Z
Li
Mengting
M
Wu
Qingan
Q
Wang
Dan
D
Feng
Hong
H
Bernard
Philip
P
Daugherty
Alan
A
Huang
Bin
B
Li
Xiang-An
XA
D000818:Animals; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D015870:Gene Expression; D006090:Gram-Negative Bacteria / Q000302:isolation & purification; D008070:Lipopolysaccharides / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000276:immunology; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D051197:Toll-Like Receptor 4 / Q000276:immunology
D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins; D016328:NF-kappa B; D051122:Scavenger Receptors, Class B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D003345:Corticosterone