title: Tissue plasminogen activator induces microglial inflammation via a noncatalytic molecular mechanism involving activation of mitogen-activated protein kinases and Akt signaling pathways and AnnexinA2 and Galectin-1 receptors.
abstract: Inflammatory responses mediated by glial cells play a critical role in many pathological situations related to neurodegeneration such as Alzheimer's disease. Tissue plasminogen activator (tPA) is a serine protease which best-known function is fibrinolysis, but it is also involved in many other physiological and pathological events as microglial activation. Here, we found that tPA is required for Aβ-mediated microglial inflammatory response and tumor necrosis factor-α release. We further investigated the molecular mechanism responsible for tPA-mediated microglial activation. We found that tPA induces a catalytic-independent rapid and sustained activation of extracellular signal-regulated kinase (ERK)1/2, Jun N-terminal kinase (JNK), Akt, and p38 signaling pathways. Inhibition of ERK1/2 and JNK resulted in a strong inhibition of microglial activation, whereas Akt inhibition led to increased inflammatory response, suggesting specific functions for each signaling pathway in the regulation of microglial activation. Furthermore, we demonstrated that AnnexinA2 and Galectin-1 receptors are involved in tPA signaling and inflammatory response in glial cells. This study provides new evidences supporting that tPA plays a cytokine-like role in glial activation by triggering receptor-mediated intracellular signaling circuits and opens new therapeutic strategies for the treatment of neurological disorders in which neuroinflammation plays a pathogenic role.
authors.affiliation: Cancer Research Programme, IMIM-Hospital del Mar, C/ Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pineda
authors.forename: Coral
authors.initials: C
authors.lastname: Ampurdanés
authors.forename: Manel G
authors.initials: MG
authors.lastname: Medina
authors.forename: Joan
authors.initials: J
authors.lastname: Serratosa
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Tusell
authors.forename: Josep
authors.initials: J
authors.lastname: Saura
authors.forename: Anna M
authors.initials: AM
authors.lastname: Planas
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037483:Galectin 1 / Q000172:deficiency / Q000378:metabolism*; D055786:Gene Knockout Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017306:Annexin A2; D004791:Enzyme Inhibitors; D037483:Galectin 1; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C023023:lipid-linked oligosaccharides; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D010959:Tissue Plasminogen Activator