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Acta Neuropathologica
Published in: Acta Neuropathologica 4/2017

Open Access 01-10-2017 | Original Paper

Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

Authors: Enming Joseph Su, Chunzhang Cao, Linda Fredriksson, Ingrid Nilsson, Christina Stefanitsch, Tamara K. Stevenson, Juanjuan Zhao, Margret Ragsdale, Yu-Yo Sun, Manuel Yepes, Chia-Yi Kuan, Ulf Eriksson, Dudley K. Strickland, Daniel A. Lawrence, Li Zhang

Published in: Acta Neuropathologica | Issue 4/2017

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Abstract

Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood–brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1−/−) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1−/− mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b+ cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1−/− mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability.
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Metadata
Title
Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke
Authors
Enming Joseph Su
Chunzhang Cao
Linda Fredriksson
Ingrid Nilsson
Christina Stefanitsch
Tamara K. Stevenson
Juanjuan Zhao
Margret Ragsdale
Yu-Yo Sun
Manuel Yepes
Chia-Yi Kuan
Ulf Eriksson
Dudley K. Strickland
Daniel A. Lawrence
Li Zhang
Publication date
01-10-2017
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 4/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1749-z

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