Scavenger receptor BI and high-density lipoprotein regulate thymocyte apoptosis in sepsis.
Scavenger receptor BI and high-density lipoprotein regulate thymocyte apoptosis in sepsis.
复制标题
清道夫受体 BI 和高密度脂蛋白调节脓毒症中胸腺细胞凋亡。
DOI：
10.1161/atvbaha.113.302484
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Li XA
中科院分区：
文献类型：
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作者：
Guo L;Zheng Z;Ai J;Howatt DA;Mittelstadt PR;Thacker S;Daugherty A;Ashwell JD;Remaley AT;Li XA
胸腺细胞凋亡是脓毒症的主要事件，然而，这一过程是如何调节仍然知之甚少。脓毒症应激诱导糖皮质激素（GC）产生，其触发胸腺细胞凋亡。在这里，我们使用清道夫受体BI（SR-BI）空小鼠，这是完全缺乏诱导型GC（iGC）在脓毒症，研究胸腺细胞凋亡的调节脓毒症。盲肠结扎和穿孔（CLP）诱导SR-BI+/+小鼠的胸腺细胞凋亡，但由于缺乏iGC，SR-BI−/−小鼠没有胸腺细胞凋亡。出乎意料的是，补充GC仅部分恢复了SR-BI−/−小鼠的胸腺细胞凋亡。我们证明HDL是胸腺细胞凋亡的关键调节剂。SR-BI+/+ HDL显著增强GC诱导的胸腺细胞凋亡，但SR-BI−/− HDL没有这种活性。进一步的研究表明，SR-BI+/+ HDL通过促进糖皮质激素受体转位来调节GC诱导的胸腺细胞凋亡，但SR-BI−/− HDL失去了这种调节活性。为了了解SR-BI−/− HDL失去调节活性的原因，我们分析了HDL胆固醇含量。与SR-BI+/+ HDL相比，SR-BI−/− HDL中未酯化胆固醇富集3倍。通过普罗布考给药或LCAT表达使SR-BI−/− HDL中的未酯化胆固醇正常化，恢复了GC诱导的胸腺细胞凋亡，并将未酯化胆固醇掺入SR-BI +/+ HDL使SR-BI +/+ HDL功能失调。使用lckCre-GRfl/fl小鼠，其中胸腺细胞缺乏CLP诱导的胸腺细胞凋亡，我们发现lckCre-GRfl/fl小鼠比GRfl/fl对照小鼠对CLP诱导的脓毒症死亡显著更敏感，这表明GC诱导的胸腺细胞凋亡是预防脓毒症所必需的。本研究揭示了SR-BI和HDL对脓毒症胸腺细胞凋亡的一种新的调控机制。
Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. Septic stress induces glucocorticoids (GC) production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI) null mice, which are completely deficient in inducible GC (iGC) in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture (CLP) induced profound thymocyte apoptosis in SR-BI+/+ mice, but no thymocyte apoptosis in SR-BI−/− mice due to lack of iGC. Unexpectedly, supplementation of 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. 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 LCAT expression restored GC-induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI+/+ HDL rendered SR-BI+/+ HDL dysfunctional. Using lckCre-GRfl/fl mice in whom thymocytes lack CLP-induced thymocyte apoptosis, we showed that lckCre-GRfl/fl mice were significantly more susceptible to CLP-induced septic death than GRfl/fl control mice, suggesting that GC-induced thymocyte apoptosis is required for protection against sepsis. The findings in this study reveal a novel regulatory mechanism of thymocyte apoptosis in sepsis by SR-BI and HDL.