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

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.

• 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
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 134 Issue 4 Pg. 585-604 (Oct 2017) ISSN: 1432-0533 [Electronic] Germany
• PMID: 28725968 (Publication Type: Journal Article)

Chemical References

• CD11b Antigen
• Fibrinolytic Agents
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• Lymphokines
• Macrophage-1 Antigen
• Platelet-Derived Growth Factor
• Receptors, LDL
• Tumor Suppressor Proteins
• platelet-derived growth factor C
• Tissue Plasminogen Activator

Topics

• Animals
• Arterioles (drug effects, metabolism, pathology)
• Blood-Brain Barrier (drug effects, metabolism, pathology)
• Bone Marrow Cells (metabolism, pathology)
• Brain Ischemia (drug therapy, metabolism, pathology)
• CD11b Antigen (metabolism)
• Capillary Permeability (drug effects, physiology)
• Cells, Cultured
• Cerebral Hemorrhage (chemically induced, metabolism, pathology)
• Disease Models, Animal
• Female
• Fibrinolytic Agents (adverse effects, pharmacology)
• Leukocytes (metabolism, pathology)
• Low Density Lipoprotein Receptor-Related Protein-1
• Lymphokines (metabolism)
• Macrophage-1 Antigen (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (metabolism, pathology)
• Platelet-Derived Growth Factor (metabolism)
• Receptors, LDL (metabolism)
• Stroke (drug therapy, metabolism, pathology)
• Tissue Plasminogen Activator (adverse effects, pharmacology)
• Tumor Suppressor Proteins (metabolism)