Abstract 271: Scavenger Receptor Bi is a Key Determinant and HDL is a Critical Modulator of Thymocyte Apoptosis in Sepsis

Background-Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood.

Methods and Results-We induced sepsis in scavenger receptor BI (SR-BI) null and wild type littermates with cecal ligation and puncture (CLP). CLP induced profound thymocyte apoptosis in SR-BI^+/+ mice, but no thymocyte apoptosis in SR-BI^-/- mice, indicating that SR-BI is a key determinant of thymocyte apoptosis in sepsis. SR-BI controlled inducible glucocorticoid (GC) generation during sepsis, which is required for triggering thymocyte apoptosis. Unexpectedly, supplementation with GC only partly restored thymocyte apoptosis in SR-BI^-/- mice. We demonstrated that HDL is a critical modulator for thymocyte apoptosis. SR-BI^+/+ HDL significantly enhanced GC-induced thymocyte apoptosis but SR-BI^-/- HDL had no such activity. Further study revealed that SR-BI^+/+ HDL modulates GC-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 and found that there was 3-fold enrichment of unesterified cholesterol in SR-BI^-/- HDL compared with SR-BI^+/+ HDL. Importantly, normalization of unesterified cholesterol in SR-BI^-/- HDL by probucol administration restored GC-induced thymocyte apoptosis both in vitro and in vivo, and incorporating unesterified cholesterol into SR-BI^+/+ HDL rendered SR-BI^+/+ HDL dysfunctional.

Conclusions-The findings in this study reveal a previously unrecognized regulatory mechanism of thymocyte apoptosis in sepsis, involving SR-BI as a key determinant and HDL as a critical modulator.