Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice

Ling Guo,Zhong Zheng,Junting Ai,Bin Huang,Xiang-An Li

doi:10.1074/jbc.m113.537258

Ling Guo, Zhong Zheng + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m113.537258

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Abstract

Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1(I179N) mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1(I179N) mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1(I179N) mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis.

Highlights

We utilized Scarb1I179N mice, a model deficient in hepatic SR-BI, to determine the role of hepatic SR-BI in sepsis
Macrophage SR-BI suppresses inflammatory response by modulating LPS-TLR4 signaling in macrophages, which contributes to protection against septic animal death [50, 52]; Adrenal SR-BI is a key determinant of inducible glucocorticoid (GC) generation in response to stress [49, 50, 53], and SR-BI null mice are completely deficient in inducible GC generation in cecal ligation and puncture (CLP)-induced sepsis [50]; A number of studies suggest that SR-BI may provide protection against sepsis through detoxifying LPS
Using Scarb1I179N mice, a unique hepatic specific SR-BI deficient mouse model, we demonstrate that hepatic SR-BI is a critical protective factor in sepsis

Summary

Background

We utilized Scarb1I179N mice, a model deficient in hepatic SR-BI, to determine the role of hepatic SR-BI in sepsis. Recent studies revealed an important function of SR-BI, namely, protection against sepsis, as shown by a marked increase in fatality in mice deficient in SR-BI upon lipopolysaccharides (LPS) or cecal ligation and puncture (CLP) challenge (48 –51). Macrophage SR-BI suppresses inflammatory response by modulating LPS-TLR4 signaling in macrophages, which contributes to protection against septic animal death [50, 52]; Adrenal SR-BI is a key determinant of inducible glucocorticoid (GC) generation in response to stress [49, 50, 53], and SR-BI null mice are completely deficient in inducible GC generation in CLP-induced sepsis [50]; A number of studies suggest that SR-BI may provide protection against sepsis through detoxifying LPS. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION