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Ex Vivo Imaging of Postnatal Cerebellar Granule Cell Migration Using Confocal Macroscopy
Published on: May 12, 2015
Urokinase-type plasminogen activator induces BV-2 microglial cell migration through activation of matrix
Sun Mi Shin1, Kyu Suk Cho, Min Sik Choi
1Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul, 151-742, Korea.
Abstract:
In response to brain injury, microglia migrate and accumulate in the affected sites, which is an important step in the regulation of inflammation and neuronal degeneration/regeneration. In this study, we investigated the effect of urokinase-type plasminogen activator (uPA) on the BV-2 microglial cell migration. At resting state, BV-2 microglial cells secreted uPA and the release of uPA was increased by ATP, a chemoattractant released from injured neuron. The migration of BV-2 cell was significantly induced by uPA and inhibited by uPA inhibitors. In this condition, uPA increased the activity of matrix metalloproteinase (MMP-9) and the inhibition of MMP activity with pharmacological inhibitors against either uPA (amiloride) or MMP (phenanthrolene and SB-3CT) effectively prevented BV2 cell migration. Interestingly, the level of MMP-9 protein and mRNA in the cell were not changed by uPA. These results suggest that the increase of MMP-9 activity by uPA is regulated at the post-translational level, possibly via increased activation of the enzyme. Unlike the uPA inhibitor, plasmin inhibitor PAI-1 only partially inhibited uPA-induced cell migration and MMP-9 activation. The incubation of recombinant MMP-9 with uPA resulted in the activation of MMP-9. These results suggest that uPA plays a critical role in BV-2 microglial cell migration by activating pro-MMP-9, in part by its direct action on MMP-9 and also in part by the activation of plasminogen/plasmin cascade.
Insights
Urokinase-type plasminogen activator (uPA) drives microglial cell migration after brain injury by activating matrix metalloproteinase-9 (MMP-9) at the post-translational level, aiding inflammation and neural repair processes.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Microglia are crucial immune cells in the brain, responding to injury by migrating to affected areas.
- This migration is vital for regulating inflammation and supporting neuronal repair or degeneration.
- The role of urokinase-type plasminogen activator (uPA) in microglial migration is not fully understood.
Purpose of the Study:
- To investigate the effect of uPA on the migration of BV-2 microglial cells.
- To elucidate the molecular mechanisms by which uPA influences microglial migration.
Main Methods:
- BV-2 microglial cells were treated with uPA and ATP (a neuronal chemoattractant).
- Cell migration was assessed in the presence and absence of uPA inhibitors and matrix metalloproteinase (MMP) inhibitors.
- MMP-9 activity, protein, and mRNA levels were measured.
- Recombinant MMP-9 was incubated with uPA to assess direct activation.
Main Results:
- BV-2 cells secrete uPA, with release enhanced by ATP.
- uPA significantly induced BV-2 cell migration, an effect inhibited by uPA and MMP inhibitors.
- uPA increased MMP-9 activity post-translationally, without altering MMP-9 protein or mRNA levels.
- PAI-1 partially inhibited uPA-induced migration and MMP-9 activation, while direct incubation of uPA with MMP-9 activated it.
Conclusions:
- uPA plays a critical role in microglial migration.
- uPA activates pro-MMP-9, partly through direct action and partly via the plasminogen/plasmin cascade.
- These findings highlight uPA as a key regulator of microglial response to brain injury.
