Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro

Several CNS disorders feature microglial activation. Microglia are known to have both restorative and cytotoxic capabilities. Neuronal apoptosis has been noted after an acute insult such as ischemia. Microglia may participate in this event. We previously showed that conditioned medium (CM) harvested from peritoneal macrophages or from activated microglia triggered apoptosis in rat hippocampal neurons in culture. We wished to characterize the factor responsible for triggering neuronal death. Quiescent microglia produced CM that did not disrupt hippocampal neurons. Lipopolysaccharide‐activated microglia produced CM which resulted in neuronal death. This effect was blocked by plasminogen activator inhibitor‐1, by tPA STOP, and by co‐incubation with tPA antibody. Recombinant human tPA exaggerated the neurotoxic effects of microglial CM, while tPA alone was toxic only at very high concentrations. This in vitro system, which probably excludes any significant impact of microglial free radicals, suggests that microglial tPA may contribute significantly to hippocampal neuronal death. GLIA 29:347–354, 2000. © 2000 Wiley‐Liss, Inc.

[1]  G. Sutherland,et al.  Electron Microscopic Evidence against Apoptosis as the Mechanism of Neuronal Death in Global Ischemia , 1999, The Journal of Neuroscience.

[2]  J. Koh,et al.  Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. , 1999, Science.

[3]  G. Zoppo.  tPA: A neuron buster, too? , 1998, Nature Medicine.

[4]  S. Lipton,et al.  Tissue plasminogen activator (tPA) increase neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice , 1998, Nature Medicine.

[5]  S. Strickland,et al.  Neuronal Death in the Hippocampus Is Promoted by Plasmin-Catalyzed Degradation of Laminin , 1997, Cell.

[6]  M. Flavin,et al.  Soluble macrophage factors trigger apoptosis in cultured hippocampal neurons , 1997, Neuroscience.

[7]  M. Flavin,et al.  Neurotoxicity of Soluble Macrophage Productsin Vitro—Influence of Dexamethasone , 1997, Experimental Neurology.

[8]  Sidney Strickland,et al.  Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator , 1995, Nature.

[9]  P. Wood,et al.  Microglia as a unique cellular target in the treatment of stroke: potential neurotoxic mediators produced by activated microglia. , 1995, Neurological research.

[10]  K. Hossmann,et al.  Reactive microglia in cerebral ischaemia: an early mediator of tissue damage? , 1995, Neuropathology and applied neurobiology.

[11]  Z. Werb,et al.  Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix , 1995, Science.

[12]  Y. Uchiyama,et al.  Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  M. Castro,et al.  In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid β-peptide analogues , 1995, Nature Medicine.

[14]  S. Koizumi,et al.  Modulatory effect of plasminogen on NMDA-induced increase in intracellular free calcium concentration in rat cultured hippocampal neurons , 1994, Neuroscience Letters.

[15]  V. Perry,et al.  Macrophages and the nervous system. , 1994, International review of cytology.

[16]  C. Robertson,et al.  Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system , 1993, Journal of neuroscience research.

[17]  C. Théry,et al.  Neurotoxicity of brain macrophages. , 1993, Clinical neuropathology.

[18]  A. Levinson,et al.  Prevention of metastasis by inhibition of the urokinase receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Thanos,et al.  Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  D. Giulian,et al.  Brain glia release factors with opposing actions upon neuronal survival , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  H. Matsuda,et al.  Hypoperfusion and Vasoreactivity in the Thalamus and Cerebellum After Stroke , 1993, Stroke.

[22]  J. Zimmer,et al.  Microglial MHC antigen expression after ischemic and kainic acid lesions of the adult rat hippocampus , 1993, Glia.

[23]  T. Molitor,et al.  Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. , 1992, Journal of immunology.

[24]  K. Frei,et al.  Macrophage‐induced cytotoxicity of N‐methyl‐D‐aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines , 1992, European journal of immunology.

[25]  S. Kohsaka,et al.  Microglia isolated from rat brain secrete a urokinase-type plasminogen activator , 1992, Brain Research.

[26]  J. Zivin,et al.  Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. , 1991, Archives of neurology.

[27]  P. Levitt,et al.  Brain macrophages and microglia respond differently to lesions of the developing and adult visual system , 1991, The Journal of comparative neurology.

[28]  C. Robertson,et al.  Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord , 1990, Annals of neurology.

[29]  D. Monard.  Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth , 1988, Trends in Neurosciences.

[30]  D. Belin,et al.  Amiloride selectively inhibits the urokinase‐type plasminogen activator , 1987, FEBS letters.

[31]  D. Belin,et al.  Concomitant secretion of prourokinase and of a plasminogen activator- specific inhibitor by cultured human monocytes-macrophages , 1984, The Journal of experimental medicine.

[32]  C. Nathan,et al.  The macrophage as an effector cell. , 1980, The New England journal of medicine.

[33]  K. McCarthy,et al.  Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue , 1980, The Journal of cell biology.

[34]  S. Pizzo,et al.  Effector mechanisms of cytolytically activated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neutral proteases. , 1980, Journal of immunology.

[35]  G. Currie.  Activated macrophages kill tumour cells by releasing arginase , 1978, Nature.

[36]  K. Frei,et al.  Antigen presentation and tumor cytotoxicity by interferon‐γ‐treated microglial cells , 1987 .

[37]  G H Sato,et al.  Growth of a rat neuroblastoma cell line in serum-free supplemented medium. , 1979, Proceedings of the National Academy of Sciences of the United States of America.