Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury.
Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury.
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DOI：
10.1111/j.1471-4159.2009.06232.x
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发表时间：
2009-09
影响因子：
4.7
通讯作者：
Popovich PG
中科院分区：
文献类型：
--
作者：
Lucin KM;Sanders VM;Popovich PG
创伤后免疫抑制使脊髓损伤（SCI）患者易受感染。正常情况下，适当的免疫功能是由交感神经系统（SNS）和下丘脑-垂体-肾上腺（HPA）轴之间的协作调节，并涉及糖皮质激素（GC）和去甲肾上腺素（NE）的控制释放。最近，我们发现在高位胸（T3）SCI后，异常水平的GC和NE分别在血液和脾脏中积累。这些变化与脾萎缩、脾白细胞减少、脾内caspase-3水平升高和B淋巴细胞功能抑制相关。由于GC促进SNS功能，部分是通过增加β-2肾上腺素能受体（β 2AR）的表达和亲和力，同时防止β2AR下调，我们预测应激激素（即，高水平脊髓损伤小鼠血液和脾脏中的GC和NE同时作用，对淋巴细胞功能和存活产生不利影响。在这里，我们发现SCI后GC浓度增加了淋巴细胞对β2AR刺激的敏感性，导致细胞内Bim（Bcl 2-Interacting Mediator of Cell Death）增加，随后发生凋亡。在体内，GC受体和β 2 AR的联合拮抗作用显著降低了淋巴细胞Bim水平和SCI诱导的脾淋巴细胞减少症。总之，这些数据表明，HPA/SNS轴的药理学拮抗剂应被视为改善四肢瘫痪和高位截瘫患者创伤后免疫抑制的辅助疗法。
Post-traumatic immune suppression renders individuals with spinal cord injury (SCI) susceptible to infection. Normally, proper immune function is regulated by collaboration between the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis and involves the controlled release of glucocorticoids (GCs) and norepinephrine (NE). Recently, we showed that after high thoracic (T3) SCI, aberrant levels of GCs and NE accumulate in the blood and spleen, respectively. These changes are associated with splenic atrophy, splenic leucopenia, increased intrasplenic caspase-3 levels and suppressed B lymphocyte function. Since GCs boost SNS function, in part by increasing the expression and affinity of beta-2 adrenergic receptors (β2ARs) while simultaneously preventing β2AR down-regulation, we predicted that surges in stress hormones (i.e., GCs and NE) in the blood and spleen of mice with high-level SCI would act concurrently to adversely affect lymphocyte function and survival. Here, we show that post-SCI concentrations of GCs enhance the sensitivity of lymphocytes to β2AR stimulation causing an increase in intracellular Bim (Bcl2-Interacting Mediator of Cell Death) and subsequent apoptosis. In vivo, the combined antagonism of GC receptors and β2ARs significantly diminished lymphocyte Bim levels and SCI-induced splenic lymphopenia. Together, these data suggest that pharmacological antagonists of the HPA/SNS axes should be considered as adjunct therapies for ameliorating post-traumatic immune suppression in quadriplegics and high paraplegics.
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