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.