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  • 1.  
  • 2. Innate and adaptive immune responses Clinical Immunology: Principles and Practice. Chapter 3: Innate Immunity. Rich et al.
  • 3. Martinon et al., 2009, Ann. Rev. Immunol. 27:229-265.
  • 4. Duprez et al. Microbes & Infect. 11:1050
  • 5. What Comprises the Innate Immune System in the CNS? Which CNS Cells Harbor Inflammasomes? What is the Regulation of the Innate Immune System After CNS Injury?
  • 6. Primary vs . secondary injury
  • 7. SCI induces increased expression and processing of IL-1  and IL-18
  • 8. SCI induces increased expression of Caspase-1, -11 and ASC
  • 9. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. (2008). J Neurosci. 28: 3404-3414
  • 10. Association of NLRP1 Proteins in Neurons
  • 11.  
  • 12. Keane et al., 2008
  • 13.  
  • 14. Confocal images of spinal cord sections demonstrating anti-ASC antibody penetration into spinal cord neurons de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. (2008). J Neurosci. 28: 3404-3414
  • 15. ASC neutralization blocks NALP1 inflammasome activity de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. (2008). J Neurosci. 28: 3404-3414
  • 16. ASC neutralization improves histopathological outcome and decreases spinal cord lesion volume de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. (2008). J Neurosci. 28: 3404-3414
  • 17. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. (2008). J Neurosci. 28: 3404-3414 Anti-ASC treatment improves functional outcomes after SCI
  • 18.  
  • 19. ASC neutralization decreases NLRP1 inflammasome activity
  • 20. ASC neutralization improves histopathological outcomes after TBI
  • 21. Conclusions
    • Injury to the CNS (SCI, TBI, Stroke) results in inflammasome activation.
    • Delivery of anti-inflammasome neutralizing antibodies decreases inflammasome activation, resulting in decreased processing of caspase-1, activation of IL-1 cytokines, histopathological improvement and leads to functional improvement after CNS injury.
    • Inflammasomes appear to be a therapeutic target to treat CNS injury.
  • 22.  
  • 23. High Extracellular K+ Activates Caspase-1 in Neuronal and Astrocytic Cultures
  • 24. Extracellular ATP Activates Caspase-1 in Human Astrocytic Cultures
  • 25. ATP-Induced Caspase-1 Activation is Blocked by BBG and Probenecid
  • 26. Pyroptosis is induced by the inflammasome, a multi-protein complex that stimulates caspase-1 cleavage
    • DNA is released from necrotic cells following trauma
    • Cell-free plasma DNA increases in trauma patients (Lam et al., 2003)
      • Increases within 20 min after injury
      • Correlates with severity of injury
      • Remains elevated (by as much as 100-fold) for up to 28 days in patients with severe injuries
    • Cell-free plasma DNA is also elevated following traumatic brain injury and stroke (Rainer et al., 2003; 2006)
  • 27. Poly(dA:dT) Induces a Dose-Dependent Innate Immune Response in Cortical Neurons
    • 14-day-old cortical neurons from E18 rat embryos
    • Stimulated with poly(dA:dT) for 3 hrs (N=5-6)
  • 28. Poly(dA:dT) Increases Expression of AIM2 Inflammasome Components
    • 14-day-old cortical neurons from E18 rat embryos
    • Stimulated with poly(dA:dT) for 3 hrs (N=5-6)
  • 29. Poly(dA:dT) Induces Assembly of the Pyroptosome and Subsequent Cell Death Cell Viability Assay Oligomerization of ASC
  • 30. Model of Neuronal Pyroptosis after CND Injury
  • 31. Summary
    • CNS cells harbor different inflammasomes.
    • Innate immune reactions contribute to pathomechanisms after CNS injury.
    • ATP, K + and dsDNA are DAMPs and activate inflammasomes in astrocytes and neurons.
    • Probenecid and BBG block inflammasome activation.
    • dsDNA induces pyroptosis in neurons in vitro.
    • Innnate immune proteins appear to be an important targets to block inflammation following CNS injury.
  • 32. Dr. Juan Pablo de Rivero Vaccari Dr. Gerhard Dahl Dr. W. Dalton Dietrich Acknowledgments Julia Minkiewicz Stephanie Bacik