Scavenger receptor BI and high-density lipoprotein regulate thymocyte apoptosis in sepsis

Ling Guo, Zhong Zheng, Junting Ai, Deborah A. Howatt, Paul R. Mittelstadt, Seth Thacker, Alan Daugherty, Jonathan D. Ashwell, Alan T. Remaley, Xiang An Li

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Objective - Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. Approach and Results - Septic stress induces glucocorticoids production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI)-null mice, which are completely deficient in inducible glucocorticoids in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture induced profound thymocyte apoptosis in SR-BI-/- mice, but no thymocyte apoptosis in SR-BI-/- mice because of lack of inducible glucocorticoids. Unexpectedly, supplementation of glucocorticoids only partly restored thymocyte apoptosis in SR-BI-/- mice. We demonstrated that high-density lipoprotein (HDL) is a critical modulator for thymocyte apoptosis. SR-BI-/- HDL significantly enhanced glucocorticoid-induced thymocyte apoptosis, but SR-BI-/- HDL had no such activity. Further study revealed that SR-BI-/- HDL modulates glucocorticoid-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI -/- HDL loses such regulatory activity. To understand why SR-BI -/- HDL loses its regulatory activity, we analyzed HDL cholesterol contents. There was 3-fold enrichment of unesterified cholesterol in SR-BI -/- HDL compared with SR-BI-/- HDL. Normalization of unesterified cholesterol in SR-BI-/- HDL by probucol administration or lecithin cholesteryl acyltransferase expression restored glucocorticoid- induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI-/- HDL rendered SR-BI-/- HDL dysfunctional. Using lckCre-GRfl/fl mice in which thymocytes lack cecal ligation and puncture-induced thymocyte apoptosis, we showed that lckCre-GRfl/fl mice were significantly more susceptible to cecal ligation and puncture-induced septic death than GRfl/fl control mice, suggesting that glucocorticoid-induced thymocyte apoptosis is required for protection against sepsis. Conclusions - The findings in this study reveal a novel regulatory mechanism of thymocyte apoptosis in sepsis by SR-BI-/- and HDL.

Original languageEnglish
Pages (from-to)966-975
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • apolipoproteins
  • apoptosis
  • lipoproteins
  • scavenger receptors, class B
  • sepsis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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