Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice

Abstract

Background In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood. Methods To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1−/− mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion. Results We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion. Conclusions Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization.

Platelet Activation and Chemokine Release Are Related to Local Neutrophil-Dominant Inflammation During Hyperacute Human Stroke

“…As strength, we provide comparative, direct, and integrative human cerebral data obtained during stroke emergency care which support the pathophysiological concept of strokeinduced "thrombo-inflammation." [1] Thereby, we shift the experimental focus from thrombo-inflammatory mechanisms during the phase of reperfusion to clinical pertinence already during the earliest phases of stroke formation under occlusive condition [5,6].…”

“…The pathobiology of acute ischemic stroke (AIS) encompasses a plethora of intertwined processes within the ischemic territory such as energy failure, excitotoxicity, anoxic depolarization, apoptosis, and, more recently recognized, neuroinflammation [1,2]. Evidence in rodents and baboons points to a prominent role of platelets and coagulation factors which accumulate early at sites of cerebral infarction [3,4], and drive inflammation-related tissue damage [5]. Human evidence supporting the causative "thromboinflammatory" interplay between thrombotic and inflammatory mechanisms within the compromised ischemic vascular compartment is not available [1], but would have profound implications regarding the relevance and adequate timing of conceptually sound add-on treatments to use before and/or after recanalization therapy for large-vessel-occlusion stroke [6][7][8].…”

T Cell Response in Ischemic Stroke: From Mechanisms to Translational Insights

“…The term "thrombo-inflammation" refers to the exacerbated infarct development after ischemic stroke mediated by T lymphocyte-platelet interactions (91). This effect is already evident in the hyperacute phase of ischemic stroke and is a major factor in the tissue loss observed in the penumbra (92). Blocking platelet glycoprotein receptor Ib (GPIb), an adhesion receptor crucial for platelet binding to the endothelium during thrombosis, can specially reduce infarction volume in the border of the penumbra immediately after 2 hours of MCAO (92).…”

“…This effect is already evident in the hyperacute phase of ischemic stroke and is a major factor in the tissue loss observed in the penumbra (92). Blocking platelet glycoprotein receptor Ib (GPIb), an adhesion receptor crucial for platelet binding to the endothelium during thrombosis, can specially reduce infarction volume in the border of the penumbra immediately after 2 hours of MCAO (92). This protective effect of platelet blockage can be observed even 24 hours after reperfusion (93,94).…”

“…Moreover, platelets facilitate T cell infiltration into the brain parenchyma. Blocking either GPIb or its ligand VWF A1 domain with an antibody, or their genetic deletion, significantly reduced the number of infiltrated T cells and infarct volume (92)(93)(94). Another platelet-born pro-infiltration factor is CD84, a soluble homophilic immunoreceptor that is shed from platelets after ischemic stroke (70).…”