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

• Published in: Acta neuropathologica Vol. 134; no. 4; pp. 585 - 604
• Main Authors: Su, Enming Joseph, Cao, Chunzhang, Fredriksson, Linda, Nilsson, Ingrid, Stefanitsch, Christina, Stevenson, Tamara K., Zhao, Juanjuan, Ragsdale, Margret, Sun, Yu-Yo, Yepes, Manuel, Kuan, Chia-Yi, Eriksson, Ulf, Strickland, Dudley K., Lawrence, Daniel A., Zhang, Li
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2017; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Arterioles; Arterioles - drug effects; Arterioles - metabolism; Arterioles - pathology; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone marrow transplantation; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Capillary Permeability - drug effects; Capillary Permeability - physiology; CD11b antigen; CD11b Antigen - metabolism; Cell activation; Cells, Cultured; Cerebral blood flow; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - metabolism; Cerebral Hemorrhage - pathology; Cerebrovascular system; Disease Models, Animal; Female; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - pharmacology; Hemorrhage; Immunofluorescence; Integrins; Ischemia; Leukocytes; Leukocytes - metabolism; Leukocytes - pathology; Low Density Lipoprotein Receptor-Related Protein-1; Lymphokines - metabolism; Mac1 protein; Macrophage-1 Antigen - genetics; Macrophage-1 Antigen - metabolism; Macrophages; Male; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Membrane permeability; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Microglia - metabolism; Microglia - pathology; Neurosciences; Original Paper; Pathology; Permeability; Phosphorylation; Platelet-derived growth factor; Platelet-Derived Growth Factor - metabolism; Receptors, LDL - metabolism; Rodents; Stroke; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology; t-Plasminogen activator; Thrombolysis; Tissue plasminogen activator; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - pharmacology; Transplantation; Tumor Suppressor Proteins - metabolism; α; Stroke; β; LRP1; Tissue plasminogen activator; CD11b/CD18; Mac-1; Platelet-derived growth factor-CC; Blood–brain barrier; αMβ2
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-017-1749-z

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.