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Type: Journal article
Title: Platelet necrosis mediates ischemic stroke outcome in mice
Author: Denorme, F.
Manne, B.K.
Portier, I.
Eustes, A.S.
Kosaka, Y.
Kile, B.T.
Rondina, M.T.
Campbell, R.A.
Citation: Blood, 2020; 135(6):429-440
Publisher: American Society of Hematology
Issue Date: 2020
ISSN: 0006-4971
Statement of
Frederik Denorme, Bhanu Kanth Manne, Irina Portier, Alicia S. Eustes, Yasuhiro Kosaka, Benjamin T. Kile, Matthew T. Rondina, and Robert A. Campbell
Abstract: Dysregulated platelet functions contribute to the development and progression of ischemic stroke. Utilizing mice with a platelet-specific deletion of cyclophilin D (CypD), a mediator of necrosis, we found that platelet necrosis regulates tissue damage and outcomes during ischemic stroke in vivo. Mice with loss of CypD in platelets (CypD(plt−/−)mice) exhibited significantly enhanced cerebral blood flow, improved neurological and motor functions, and reduced ischemic stroke infarct volume after cerebral ischemia-reperfusion injury. These effects were attributable, at least in part, to platelet-neutrophil interactions. Twenty-four hours after stroke, significantly more circulating platelet-neutrophil aggregates (PNAs) were found in CypD(plt+/+) mice. Underscoring the role of platelet necrosis in PNA formation, we observed a significant number of phosphatidylserine (PS)⁺ platelets in PNAs in CypD(plt+/+) mice. In contrast, significantly fewer platelets in PNAs were PS+ in CypD(plt−/−) counterparts. Accordingly, mice with CypD-deficient platelets had fewer neutrophils and PNAs recruited to their brain following stroke relative to wild-type counterparts. Neutrophil depletion in wild-type mice conferred protection from ischemic stroke to a similar degree as observed in mice with CypD-deficient platelets. Neutrophil depletion in CypD(plt−/−) mice did not further reduce infarct size. Transmission electron microscopy of ex vivo–formed PNAs revealed a propensity of necrotic platelets to interact with neutrophils. These results suggest that necrotic platelets interact with neutrophils to exacerbate brain injury during ischemic stroke. Because inhibiting platelet necrosis does not compromise hemostasis, targeting platelet CypD may be a potential therapeutic strategy to limit brain damage following ischemic stroke.
Keywords: Blood platelets
Rights: Copyright ©2020 by American Society of Hematology
DOI: 10.1182/blood.2019002124
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