Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation

Abstract

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.

Remote Postischemic Conditioning Promotes Stroke Recovery by Shifting Circulating Monocytes to CCR2+Proinflammatory Subset

“…The RLCinduced beneficial effect was eliminated in mice that received CCR2-deficient monocytes, demonstrating a critical role of CCR2 ϩ monocytes for RLC-induced functional benefits. Consistent with our observation, a recent study addressing RLC effect in hemorrhagic stroke also showed that RLC-enhanced hematoma resolution was abolished in the absence of myeloid cells (Vaibhav et al, 2018), further supporting the role of circulating immune cells for the RLC-induced protective mechanism. One limitation of CCR2 KO adoptive transfer experiments is that we did not fully deplete CCR2 ϩ monocytes from the host mice.…”

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

“…The inflammatory mediators released post-TBI not only alter the residential CNS cells, but also recruit peripheral cells into the brain. These immune cells polarize toward pro-or anti-inflammatory phenotypes due to surrounding signals from the tissue microenvironment [ 194 , 205 , 209 , 210 ]. In cortical impact TBI models, neutrophils are among the first cell types to respond to injury.…”

“…These mechanisms may also activate mitochondrial ATP-sensitive potassium channels [ 309 ] that can restore the mitochondrial membrane potential and can suppress apoptosis following ischemia-reperfusion [ 310 ]. Recently, we reported that RIC improved hematoma resolution in a murine model of intracerebral hemorrhage (ICH) via modulation of AMP-activated protein kinase (AMPK) in macrophages [ 210 ]. RIC is gaining popularity, and more and more research has started focusing on this method in an effort to enhance endogenous protection [ 311 , 312 , 313 , 314 , 315 ].…”

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

“…Notably, several papers showed that a main mechanism of action of MSCs from adipose tissue, is to promote tissue regeneration through M2 polarization [38][39][40], but hypoxia reduces their capability to polarize macrophages in the M2 phenotype [41] while for the PB-MNCs hypoxia is a physiological trigger for angiogenesis [42][43][44][45][46].…”