Microglia are both a source and target of extracellular cyclophilin A
Gurkiran Kaur Flora1,2, Ryan S Anderton1,2,3, Bruno P Meloni1,2,4
1Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia.
Abstract:
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.
Insights
Microglia secrete cyclophilin A (CypA) in response to inflammatory and oxidative stress. Recombinant CypA (rCypA) promotes microglial survival and migration, potentially influencing the glioblastoma tumor microenvironment.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- Glioblastoma (GBM) pathogenesis is influenced by its pro-tumorigenic microenvironment.
- Microglia are key cellular components within the GBM microenvironment.
- Cyclophilin A (CypA) is a secreted protein with chemokine and cytoprotective functions, signaling through CD147.
Purpose of the Study:
- To investigate if microglia mediate pro-tumorigenic properties in GBM via CypA.
- To assess CypA expression and secretion in microglia under inflammatory and oxidative stress.
- To determine the effects of recombinant CypA (rCypA) on microglial cell behavior and signaling.
Main Methods:
- Assessed intracellular and secreted CypA expression in human primary microglia and BV2 microglial cells.
- Treated cells with lipopolysaccharide (LPS) and LY83583 to induce inflammatory and oxidative stress.
- Utilized Western blot and ELISA to analyze cell signaling pathways (ERK1/2, AKT, IκB degradation) and IL-6 secretion.
- Measured microglial wound healing and cell death in response to rCypA.
Main Results:
- Human primary microglia and BV2 cells express both CypA and CD147.
- BV2 microglial cells secreted CypA upon stimulation with pro-inflammatory and oxidative agents.
- rCypA dose-dependently enhanced microglial wound healing and reduced basal cell death.
- rCypA treatment led to increased microglial viability and chemotaxis.
Conclusions:
- Microglia secrete CypA in response to inflammatory and oxidative stress.
- rCypA acts as a pro-survival chemokine for microglia.
- CypA signaling in microglia may play a significant role in modulating the glioblastoma tumor microenvironment.
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