title: Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity.
abstract: BACKGROUND
  Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of urokinase type plasminogen activators (uPA) and tissue type plasminogen activators (tPA), which mediate fibrinolysis. PAI-1 is also involved in the innate immunity by regulating cell migration and phagocytosis. However, little is known about the role of PAI-1 in the central nervous system.
  
  
  METHODS
  In this study, we identified PAI-1 in the culture medium of mouse mixed glial cells by liquid chromatography and tandem mass spectrometry. Secretion of PAI-1 from glial cultures was detected by ELISA and western blotting analysis. Cell migration was evaluated by in vitro scratch-wound healing assay or Boyden chamber assay and an in vivo stab wound injury model. Phagocytic activity was measured by uptake of zymosan particles.
  
  
  RESULTS
  The levels of PAI-1 mRNA and protein expression were increased by lipopolysaccharide and interferon-γ stimulation in both microglia and astrocytes. PAI-1 promoted the migration of microglial cells in culture via the low-density lipoprotein receptor-related protein (LRP) 1/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 axis. PAI-1 also increased microglial migration in vivo when injected into mouse brain. PAI-1-mediated microglial migration was independent of protease inhibition, because an R346A mutant of PAI-1 with impaired PA inhibitory activity also promoted microglial migration. Moreover, PAI-1 was able to modulate microglial phagocytic activity. PAI-1 inhibited microglial engulfment of zymosan particles in a vitronectin- and Toll-like receptor 2/6-dependent manner.
  
  
  CONCLUSIONS
  Our results indicate that glia-derived PAI-1 may regulate microglial migration and phagocytosis in an autocrine or paracrine manner. This may have important implications in the regulation of brain microglial activities in health and disease.
authors: Department of Pharmacology, Brain Science & Engineering Institute, CMRI, Kyungpook National University School of Medicine, 101 Dong-In, Daegu, Joong-gu, 700-422, South Korea.
authors: Hyejin
authors: H
authors: Jeon
authors: Jong-Heon
authors: JH
authors: Kim
authors: Jae-Hong
authors: JH
authors: Kim
authors: Won-Ha
authors: WH
authors: Lee
authors: Myung-Shik
authors: MS
authors: Lee
authors: Kyoungho
authors: K
authors: Suk
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000166:cytology* / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human