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

• Type of Material: Article
• Authors: Enming Joseph Su, University of Michigan; Chunzhang Cao, University of Maryland; Linda Fredriksson, Karolinska Institutet; Ingrid Nilsson, Karolinska Institutet; Christina Stefanitsch, Karolinska Institutet; Tamara K. Stevenson, University of Michigan; Juanjuan Zhao, University of Maryland; Margret Ragsdale, University of Michigan; Yu-Yo Sun, Emory University; Manuel Yepes, Emory University; Chia-Yi Kuan, Emory University; Ulf Eriksson, Karolinska Institutet; Dudley K. Strickland, University of Maryland; Daniel A. Lawrence, University of Michigan; Li Zhang, University of Maryland
• Language: English
• Date: 2017-07-19
• Publisher: Springer Verlag (Germany)
• Publication Version: Final Published Version
• Copyright Statement: © 2017, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00401-017-1749-z
• Title of Journal or Parent Work: Acta Neuropathologica
• ISSN: 0001-6322
• Volume: 134
• Issue: 4
• Start Page: 585
• End Page: 604
• Grant/Funding Information: This work was supported by National Institutes of Health Grants HL-055374, NS-079639, HL-054710, (to D.A. Lawrence); HL-114379, HL-120388 and HL-054710 (to D. Strickland); NS-082607 and HL-054710 (to L. Zhang); and Grants from the Novo Nordisk Foundation, The Swedish Heart and Lung Foundation 2012-0077, The Swedish Cancer Foundation 2014/630, and The Swedish Research Council 2011-3861 (to U. Eriksson).
• Keywords: BLOOD-BRAIN-BARRIER; IMATINIB TREATMENT; INTRACEREBRAL HEMORRHAGE; CENTRAL-NERVOUS-SYSTEM; LRP1; FACTOR-ALPHA RECEPTOR; SUBSTRATE-SPECIFICITY; Neurosciences; Tissue plasminogen activator; Platelet-derived growth factor-CC; FOCAL CEREBRAL-ISCHEMIA; Mac-1; CD11b/CD18; Life Sciences & Biomedicine; INNATE IMMUNITY; Blood-brain barrier; DENSITY-LIPOPROTEIN RECEPTOR; Neurosciences & Neurology; Science & Technology; TISSUE-PLASMINOGEN ACTIVATOR; Stroke; Clinical Neurology; Pathology; alpha(M)beta(2)
• Research Categories: Chemistry, Biochemistry; Biology, Neuroscience

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.