title: Scavenger receptor BI and high-density lipoprotein regulate thymocyte apoptosis in sepsis.
abstract: OBJECTIVE
  Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood.
  
  
  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.
authors.affiliation: From the Department of Pediatrics (L.G., Z.Z., J.A., X.-A.L.), Graduate Center for Nutritional Sciences (Z.Z., J.A., X.-A.L.), and Saha Cardiovascular Research Center (D.A.H., A.D., X.-A.L.), University of Kentucky College of Medicine, Lexington; and Laboratory of Immune Cell Biology, National Cancer Institute (P.R.M., J.D.A.) and Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute (S.T., A.T.R.), National Institutes of Health, Bethesda, MD.
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Junting
authors.initials: J
authors.lastname: Ai
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Howatt
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mittelstadt
authors.forename: Seth
authors.initials: S
authors.lastname: Thacker
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Xiang-An
authors.initials: XA
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002432:Cecum / Q000382:microbiology / Q000601:surgery; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood*; D003345:Corticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008026:Ligation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology; D021381:Protein Transport; D011677:Punctures; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000097:blood / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction; D060168:Thymocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D008076:Cholesterol, HDL; D011965:Receptors, Glucocorticoid; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D011341:Probucol; D003345:Corticosterone
keywords: apolipoproteins; apoptosis; lipoproteins; scavenger receptors, class B; sepsis