Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA.
Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA.
J Exp Med. 2018 Oct 1;215(10):2636-2654. doi: 10.1084/jem.20171905. Epub 2018 Sep 6.
Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
自发性脑出血 (ICH) 是所有脑卒中亚型中急性死亡率最高、预后最差的一种。血肿量是ICH 患者预后的独立决定因素，因此清除血肿是临床治疗的主要目标。在此，远程肢体缺血后处理（RIC），即在肢体上反复充气放气以增加血流量，可加速脑出血后小鼠血肿的吸收和神经功能的恢复。联体动物研究表明，RIC 通过体液介导的机制加速了血栓的溶解。虽然 RIC 增加了抗炎型巨噬细胞的激活，但髓系细胞耗竭消除了 RIC 对脑出血后的有益作用。髓系特异性 AMPKα1 失活，减弱了 RIC 诱导的抗炎型巨噬细胞极化和血肿吸收，为 RIC 与免疫激活之间提供了分子联系。最后，嵌合体研究表明 RIC 介导的脑出血后神经功能恢复与髓系 CD36 表达有关。因此，RIC 作为一种临床耐受良好的治疗方法，通过非侵入性调节固有免疫反应来改善 ICH 患者的预后。此外，免疫代谢变化可能为临床监测 RIC 的治疗效果提供药效学血液生物标志物。
