Abstract
Abstract Hemorrhagic complications represent a major limitation of thrombolytic therapy with tissue plasminogen activator (tPA) in patients with ischemic stroke. Here we report that tPA induces a swift surge of circulating neutrophils and T cells in both ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury and increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved by using a sphingosine-1-phosphate receptor 1 modulator RP101075 and a CCL2 synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. Our study suggests that immune invasion of the neurovascular unit represents a previously unrecognized mechanism governing the emergence of tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.
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