Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke

Mohamad El Amki, Chaim Glück, Nadine Binder, William Middleham, Matthias T Wyss, Tobias Weiss, Hanna Meister, Andreas Luft, Michael Weller, Bruno Weber, Susanne Wegener
2020
Despite successful clot retrieval in large vessel occlusion stroke, 50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due
more » ... o microvascular obstruction of 20%-30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke. Graphical Abstract Highlights d Reperfusion failure despite clot retrieval leads to unfavorable outcome in stroke d In the thrombin model of stroke, z30% capillaries remain occluded after thrombolysis d Capillaries are plugged by neutrophils, hindering blood flow d Neutrophil depletion facilitates capillary reperfusion and stroke recovery SUMMARY Despite successful clot retrieval in large vessel occlusion stroke, $50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of $20%-30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke.
doi:10.5167/uzh-191145 fatcat:nkran56brvd2ncassonkqgp2zm