Keane, Robert

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Keane, Robert

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

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