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Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II
Chia-Jen Siao1, Stella E Tsirka
1Department of Pharmacological Sciences and Program in Molecular and Cellular Pharmacology, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651, USA.
Abstract:
Microglia are the immunocompetent cells of the CNS, and their activation is thought to play an important neurotoxic role in many diseases modeled by glutamate-induced excitotoxicity. One molecule whose expression is upregulated after excitotoxic injury is tissue plasminogen activator (tPA), a serine protease with dual roles in the CNS. The catalytic activity of tPA, which converts plasminogen into plasmin, leads to neuronal death during excitotoxicity. Via a nonproteolytic mechanism, tPA also mediates microglial activation. We show here in culture studies that stimulated wild-type neurons and microglia can release the tPA that elicits the activation, and that tPA acts in combination with other factors. We also show that the finger domain of tPA is necessary to trigger the activation and identify annexin II as its probable binding partner-receptor. Together, these findings suggest that tPA released by either neurons or microglia can act as a neural cytokine, signaling through annexin II to activate microglia in settings of disease and injury. Developing methods to inhibit the interaction of tPA with annexin II would offer a new and selective approach to interfere with microglial activation for therapeutic purposes.
Insights
Tissue plasminogen activator (tPA) activates microglia via a nonproteolytic mechanism, binding to annexin II. Inhibiting this interaction offers a therapeutic target for CNS diseases involving microglial activation.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia are key immune cells in the central nervous system (CNS).
- Microglial activation contributes to neurotoxicity in conditions like excitotoxicity.
- Tissue plasminogen activator (tPA) expression increases after CNS injury.
Purpose of the Study:
- To investigate the role of tPA in microglial activation.
- To identify the mechanism and binding partners of tPA in microglial activation.
- To explore tPA-annexin II interaction as a therapeutic target.
Main Methods:
- In vitro studies using cultured neurons and microglia.
- Analysis of tPA's role in microglial activation.
- Identification of tPA's binding partner using molecular techniques.
Main Results:
- Stimulated neurons and microglia release tPA, mediating microglial activation.
- tPA activates microglia through a nonproteolytic pathway.
- The finger domain of tPA is crucial for activation, binding to annexin II.
Conclusions:
- tPA acts as a neural cytokine, activating microglia via annexin II.
- Targeting the tPA-annexin II interaction could offer a novel therapeutic strategy for CNS diseases.
- This pathway is relevant in disease and injury settings involving microglial activation.