Microglia are both a source and target of extracellular cyclophilin A
Gurkiran Kaur Flora,
Ryan S. Anderton,
Bruno P. Meloni,
Gilles J. Guillemin,
Neville W. Knuckey,
Gabriella MacDougall,
Vance Matthews,
Sherif Boulos
Affiliations
Gurkiran Kaur Flora
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia; Perron Institute for Neurological and Translational Sciences, QEII Medical Centre, Nedlands, Western Australia, Australia; Corresponding author.
Ryan S. Anderton
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia; Perron Institute for Neurological and Translational Sciences, QEII Medical Centre, Nedlands, Western Australia, Australia; School of Health Sciences and Institute for Health Research, Fremantle, University of Notre Dame Australia, Australia
Bruno P. Meloni
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia; Perron Institute for Neurological and Translational Sciences, QEII Medical Centre, Nedlands, Western Australia, Australia; Department of Neurosurgery, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia, Australia
Gilles J. Guillemin
Neuroinflammation Group, Faculty of Medicine and Health Sciences, 2 Technology Place, Macquarie University, New South Wales, Australia
Neville W. Knuckey
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia; Perron Institute for Neurological and Translational Sciences, QEII Medical Centre, Nedlands, Western Australia, Australia; Department of Neurosurgery, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia, Australia
Gabriella MacDougall
Perron Institute for Neurological and Translational Sciences, QEII Medical Centre, Nedlands, Western Australia, Australia; School of Health Sciences and Institute for Health Research, Fremantle, University of Notre Dame Australia, Australia
Vance Matthews
School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
Sherif Boulos
Perron Institute for Neurological and Translational Sciences, QEII Medical Centre, Nedlands, Western Australia, Australia
Glioblastoma (GBM) are lethal primary brain tumours whose pathogenesis is aided, at least partly, via a pro-tumorigenic microenvironment. This study investigated whether microglia, a cell component of the GBM microenvironment, mediates pro-tumorigenic properties via the action of cyclophilin A (CypA), a potent secretable chemokine and cytoprotectant that signals via the cell surface receptor, CD147. To this end, intracellular and secreted CypA expression was assessed in human primary microglia and BV2 microglial cells treated with the endotoxin, lipopolysaccharide (LPS) and the oxidative stress inducer, LY83583. We report that human primary microglia and BV2 microglia both express CypA and CD147, and that BV2 microglial cells secrete CypA in response to pro-inflammatory and oxidative stimuli. We also demonstrate for the first time that recombinant CypA (rCypA; 1nM–1000nM) dose-dependently increased wound healing and reduced basal cell death in BV2 microglial cells. To determine the cell–signalling pathways involved, we probed microglial cell lysates for changes in ERK1/2 and AKT phosphorylation, IκB degradation, and IL-6 secretion using Western blot and ELISA analysis. In summary, BV2 microglial cells secrete CypA in response to inflammatory and oxidative stress, and that rCypA increases cell viability and chemotaxis. Our findings suggest that rCypA is a pro-survival chemokine for microglia that may influence the GBM tumour microenvironment.
