The Roles Of Caveolin-1 And Scavenger Receptor BI In Sepsis

PartⅠCaveolin-1 Protects against Sepsis through Modulating Inflammatory Response, Alleviating Bacterial Burden and Suppressing Thymocyte ApoptosisSepsis is a leading cause of death which is characterized by uncontrolled inflammatory response. In this study, we report that caveolin-1, a major component of caveolae, is a critical survival factor of sepsis. We induced sepsis using a well-established sepsis animal model, cecal ligation and puncture (CLP). CLP induced 67% fatality in caveolin-1 null mice, but only 27% fatality in wild type littermates (p =0.015). Further studies revealed that mice deficient in caveolin-1 exhibited marked increase in TNF-a and IL-6 production 20 h following CLP treatment, indicating uncontrolled inflammatory responses in the absence of caveolin-1; Caveolin-1 null mice also had significant increase in bacteria number recovered from liver and spleen, indicating elevated bacterial burdens; In addition, caveolin-1 null mice had 2-fold increase in thymocyte apoptosis compared to wild type littermates, indicating caveolin-1 as a critical modulator of thymocyte apoptosis during sepsis. In conclusion, our findings demonstrate that caveolin-1 is a critical protective modulator of sepsis in mice. Caveolin-1 exerts its protective function likely through its roles in modulating inflammatory response, alleviating bacterial burdens and suppressing thymocyte apoptosis.PartⅡScavenger Receptor BI Protects against Septic Death through Its Role in Modulating Inflammatory ResponseSepsis 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-κB 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.