An intravascular perspective on hyper-acute neutrophil, T-cell and platelet responses: Similarities between human and experimental stroke

Abstract

In stroke patients, local sampling of pial blood within the occluded vasculature before recanalization by mechanical thrombectomy emerged as powerful tool enabling insights into ultra-early stroke pathophysiology. Thereby, a strong intravascular inflammatory response hallmarked by hyper-acute neutrophil recruitment, altered lymphocyte composition and platelet activation could be observed. These human findings mirror experimental stroke. Here, neutrophil and T-cell activation are driven by platelets involving engagement of platelet glycoprotein receptor (GP)Ib, GPVI and CD84 as well as α-granule release orchestrating infarct progression. Thus, targeting of early intravascular inflammation may evolve as a new therapeutic strategy to augment the effects of recanalization.

MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study

“…The most likely explanation for these findings lies in the fact that cerebral ischaemia, both in clinical and experimental context, elicits an immediate intravascular inflammatory response, which is dominated by neutrophils, 18 , 20 and known to contribute to infarct progression under vascular occlusion, as well as during ischaemia/reperfusion injury. 6 , 39 Recently, high quantities of the platelet-derived neutrophil-activating chemokine CXC motif ligand (CXCL) 4, and the neutrophil attractant CXCL7 have been detected in human pial blood.…”

“… 40 Therefore, our current findings support a sequence of intravascular events by which platelet activation and alpha-granule release drives neutrophil degranulation and release of MMP-9 with ensuing disturbance of the BBB. 11 , 12 , 20 These inflammatory processes may perpetuate into the recanalisation phase, thereby explaining the potential prognostic utility of ultra-early local MMP-9 concentrations. This may have multiple implications for research in acute ischaemic stroke.…”

“… 35 Together, these findings challenge the concept that mainly brain-derived MMP-9 is involved in massive BBB opening and drive attention to regional neutrophil heterogeneity, and an early mode of action from the luminal side of the occluded vascular territory. 11 , 20 …”

“…Recent evidence suggests that large-vessel ischaemic stroke elicits a rapidly evolving intravascular inflammatory response, which is carried into the ischaemic territory by retrograde collateral supply through pial anastomoses, and dominated by neutrophils. 18 , 19 , 20 Retrogradely invading immune cells such as neutrophils represent a potential source of MMPs. 11 We therefore aimed to investigate whether MMP-9 and/or MMP-2 are released into collateral blood vessels at ultra-early time points and predict the formation of space-occupying parenchymal haematomas, and severe disability or death before therapeutic recanalisation by EVT.…”

Delayed NLRP3 inflammasome inhibition ameliorates subacute stroke progression in mice

“…Cerebral ischemia elicits a strong neuroinflammatory response which occurs in a strict spatio-temporal order [1]. During the first 24 h inflammation is mainly restricted to the intravascular compartment [2], probably driven by local platelet and leukocyte derived danger-associated molecular patterns (DAMPs) and chemokines [3,4]. A second inflammatory wave is induced by neuronal and glial cell death with ensuing infiltration of immune cells into the brain parenchyma [5,6].…”