Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma
Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma
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DOI：
10.1038/s41467-020-17565-y
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发表时间：
2020-07-27
影响因子：
16.6
通讯作者：
Gaudilliere, Brice
中科院分区：
文献类型：
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作者：
Ganio, Edward A.;Stanley, Natalie;Gaudilliere, Brice
糖皮质激素（GC）是临床治疗急性炎症（包括败血症或创伤性损伤）的一种有争议但常用的干预措施。在诸如手术等重大创伤的背景下，人们对GC的不良反应提出了关注，因此有必要更好地了解GC如何调节免疫反应。在此，我们报告了一项随机对照试验（NCT02542592）的结果，在该试验中，我们采用高维质量细胞术方法来表征接受安慰剂或甲基强龙（MP）治疗的患者在大手术（主要结局）后的先天和适应性细胞信号动力学。结合随机森林分析的免疫细胞亚群的鲁棒无监督自引导聚类显示了mp诱导的免疫细胞信号传导轨迹的深刻改变（AUC=0.92， p值=3.16E-8），特别是在适应性区室中。相比之下，先前与手术后疼痛和功能恢复相关的关键先天信号反应，包括STAT3和CREB磷酸化，不受MP的影响。这些结果暗示了GCs的细胞特异性和途径特异性作用，也提示了未来的研究，以检验GCs对临床结果的影响可能依赖于功能性适应性免疫反应。
Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC=0.92, p-value=3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs' effects on clinical outcomes likely dependent on functional adaptive immune responses.