Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II.
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.
Siao
Chia-Jen
CJ
Department of Pharmacological Sciences and Program in Molecular and Cellular Pharmacology, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651, USA.
Tsirka
Stella E
SE
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D017306:Annexin A2; D000943:Antigens, Differentiation; D011994:Recombinant Proteins; C036763:monocyte-macrophage differentiation antigen; D010959:Tissue Plasminogen Activator