Deng Haoyu, Liang Wan Yi, Chen Leqi, Huang Kate, Mccallum Rylan, Rensen Patrick C N, Boyd John H, Trinder Mark, Brunham Liam R
Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Centre for Heart and Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
Department of Microbiology and Immunology, Faculty of Science, University of British Columbia, Vancouver, BC, Canada.
J Lipid Res. 2025 Jul 5;66(8):100858. doi: 10.1016/j.jlr.2025.100858.
Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather were HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation.
脓毒症是对感染的免疫反应失调，是导致死亡的主要原因。高密度脂蛋白（HDL）胆固醇水平低与脓毒症死亡风险增加相关，在脓毒症小鼠模型中，通过抑制胆固醇酯转运蛋白（CETP）来提高HDL水平已显示可降低死亡率。本研究的目的是探讨CETP抑制和HDL导致脓毒症期间生存率提高的细胞机制。我们发现在脓毒症小鼠模型中，HDL抑制脂多糖（LPS）诱导的IL-1β激活。IL-1β的激活依赖于B类1型清道夫受体（SR-B1）的活性，敲低SR-B1可显著减弱LPS诱导的巨噬细胞中IL-1β的产生。此外，我们发现LPS诱导的SR-B1内化通过内体-溶酶体途径发生，这也可能是巨噬细胞中LPS降解的原因。此外，我们发现通过CETP抑制提高HDL可显著增强HDL介导的对LPS刺激的抗炎作用，这些作用不是由于CETP本身，而是依赖于HDL。最后，我们表明，药理学抑制CETP可通过抑制LPS注射后肝脏和循环中IL-1β的产生，显著改善内毒素血症诱导的死亡率。病理上，CETP抑制减弱了LPS诱导的弥漫性肺泡损伤和肝细胞坏死，这可能有助于使用CETP抑制剂阿那曲泊帕治疗的小鼠死亡率的改善。综上所述，我们的研究结果揭示了一种细胞机制，即HDL通过SR-B1介导的LPS降解减弱LPS诱导的促炎反应。
