Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation.
Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation.
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DOI：
10.1084/jem.20171905
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Dhandapani KM
中科院分区：
文献类型：
--
作者：
Vaibhav K;Braun M;Khan MB;Fatima S;Saad N;Shankar A;Khan ZT;Harris RBS;Yang Q;Huo Y;Arbab AS;Giri S;Alleyne CH Jr;Vender JR;Hess DC;Baban B;Hoda MN;Dhandapani KM
脑出血是一种破坏性的神经损伤，导致患者预后不良。在这份报告中，Vaibhav等人证明了远程缺血后处理通过增强AMPK依赖性替代巨噬细胞活化非侵入性地加速血肿消退。自发性脑出血（ICH）是所有卒中亚型中急性死亡率最高、预后最差的。血肿体积是ICH患者结局的独立决定因素，因此凝块消退是临床管理的主要目标。在此，远端肢体缺血后处理（RIC），肢体上血压袖带的重复充气-放气，加速了小鼠ICH后的血肿消退和改善的神经学结局。共生研究表明，RIC通过体液介导的机制加速凝块消退。尽管RIC增加了抗炎巨噬细胞活化，但髓样细胞耗竭消除了ICH后RIC的有益作用。代谢调节因子AMPKα1的骨髓特异性失活，减弱了RIC诱导的抗炎巨噬细胞极化和延迟血肿消退，提供了RIC和免疫激活之间的分子联系。最后，嵌合体研究表明髓系CD 36表达与ICH后RIC介导的神经功能恢复有关。因此，RIC是一种临床耐受性良好的治疗方法，可非侵入性调节先天性免疫反应，以改善ICH结局。此外，免疫代谢变化可提供药效学血液生物标志物，以临床监测RIC的治疗效果。
Intracerebral hemorrhage is a devastating neurological injury that produces poor patient outcomes. In this report, Vaibhav et al. demonstrate that remote ischemic post-conditioning noninvasively accelerates hematoma resolution by enhancing AMPK-dependent alternative macrophage activation. 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.
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