A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain

• Type of Material: Article
• Authors: Ariel Diaz, Emory University; Paola Merino, Emory University; Luis Guillermo Manrique, Emory University; Juan Pablo Ospina, Emory University; Lihong Cheng, Emory University; Fang Wu, Emory University; Valerie Jeanneret, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2017-10-25
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2017 the authors
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1630-17.2017
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 37
• Issue: 43
• Start Page: 10310
• End Page: 10322
• Grant/Funding Information: This work was supported in part by the National Institutes of Health (Grant NS-091201 to M.Y. and Grant NS-079331 to M.Y.) and the Veterans Administration (MERIT Award IO1BX003441 to M.Y.).
• Keywords: Astrogliosis; Recovery; Urokinase-type plasminogen activator; Plasmin; Neurorepair
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin on the cell surface. Our previous studies indicate that uPA and uPAR expression increase in the ischemic brain during the recovery phase from an acute ischemic injury and that uPA binding to uPAR promotes neurological recovery after an acute ischemic stroke. Here, we used male mice genetically deficient on either uPA (uPA−/−) or uPAR (uPAR−/−) or with a four-amino acid substitution into the growth factor domain of uPA that abrogates its binding to uPAR (PlatGFDhu/GFDhu) to investigate the mechanism whereby uPA promotes neurorepair in the ischemic brain. We found that neurons release uPA and astrocytes recruit uPAR to their plasma membrane during the recovery phase from a hypoxic injury and that binding of neuronal uPA to astrocytic uPAR induces astrocytic activation by a mechanism that does not require plasmin generation, but instead is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-regulated phosphorylation of the signal transducer and activator of transcription 3 (STAT3). We report that uPA/uPAR binding is necessary and sufficient to induce astrocytic activation in the ischemic brain and that astrocytes activated by neuronal uPA promote synaptic recovery in neurons that have suffered an acute hypoxic injury via a mechanism mediated by astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). In summary, we show that uPA/uPAR-induced astrocytic activation mediates a cross talk between astrocytes and injured neurons that promotes synaptic recovery in the ischemic brain.