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

Arterioscler Thromb Vasc Biol. 2014 May;34(5):966-75. doi: 10.1161/ATVBAHA.113.302484. Epub 2014 Mar 6.

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-GR(fl/fl) mice in which thymocytes lack cecal ligation and puncture-induced thymocyte apoptosis, we showed that lckCre-GR(fl/fl) mice were significantly more susceptible to cecal ligation and puncture-induced septic death than GR(fl/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.

Keywords: apolipoproteins; apoptosis; lipoproteins; scavenger receptors, class B; sepsis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cecum / microbiology
  • Cecum / surgery
  • Cells, Cultured
  • Cholesterol, HDL / blood*
  • Corticosterone / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Ligation
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphatidylcholine-Sterol O-Acyltransferase / genetics
  • Phosphatidylcholine-Sterol O-Acyltransferase / metabolism
  • Probucol / pharmacology
  • Protein Transport
  • Punctures
  • Receptors, Glucocorticoid / metabolism
  • Scavenger Receptors, Class B / deficiency
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism*
  • Sepsis / blood
  • Sepsis / metabolism*
  • Sepsis / microbiology
  • Sepsis / pathology
  • Signal Transduction
  • Thymocytes / drug effects
  • Thymocytes / metabolism*
  • Thymocytes / pathology

Substances

  • Cholesterol, HDL
  • Receptors, Glucocorticoid
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Phosphatidylcholine-Sterol O-Acyltransferase
  • Probucol
  • Corticosterone