Molecular Mechanisms Underlying Severe Sepsis: Insights from Epigenetics

  • W. F. CarsonIV
  • S. L. Kunkel
Part of the Annual Update in Intensive Care and Emergency Medicine book series (AUICEM, volume 2012)


Recent investigations into the pathogenesis of severe sepsis, septic shock, burn, stroke and ischemia/reperfusion injury have identified common patterns of disease. Despite their disparate etiologies, these syndromes share many similar immunological outcomes. In particular, survivors of life-threatening shock syndromes often exhibit decreased long-term survival rates as compared to the healthy age-matched population [1]. This decrease in survival often correlates with an increased susceptibility to secondary, nosocomial and opportunistic infections [2, 3]. In addition, survivors of severe shock and trauma often exhibit immunosuppressive phenotypes, particularly in regards to cellular immune activation and effector function. These phenotypes can be observed both in human patients and in animal models of severe inflammation and injury, specifically in animal models of severe sepsis [4]. Severe injury and inflammation are often associated with widespread apoptosis; the immunosuppression observed following these events is often ascribed to this loss of immune cells [5]. However, these deficiencies often persist despite the eventual return of immune cells to preinjury levels in peripheral blood and immune organs [6]. The focus of current research into sepsis and shock-induced immunosuppression has been to elucidate the molecular mechanisms underlying the persistent immunosuppressive state in cells that have survived both the acute phase of the disease, and have recovered after the widespread apoptotic event.


Septic Shock Severe Sepsis Histone Modification Systemic Inflammatory Response Syndrome Epigenetic Mechanism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Winters BD, Eberlein M, Leung J, et al (2010) Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med 38: 1276–1283PubMedGoogle Scholar
  2. 2.
    Landelle C, Lepape A, Francais A, et al (2008) Nosocomial infection after septic shock among intensive care unit patients. Infect Control Hosp Epidemiol 29: 1054–1065PubMedCrossRefGoogle Scholar
  3. 3.
    Landelle C, Lepape A, Voirin N, et al (2010) Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 36: 1859–1866PubMedCrossRefGoogle Scholar
  4. 4.
    Benjamim CF, Hogaboam CM, Kunkel SL (2004) The chronic consequences of severe sepsis. J Leukoc Biol 75: 408–412PubMedCrossRefGoogle Scholar
  5. 5.
    Tinsley KW, Grayson MH, Swanson PE, et al (2003) Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol 171: 909–914PubMedGoogle Scholar
  6. 6.
    Wen H, Dou Y, Hogaboam CM, Kunkel SL (2008) Epigenetic regulation of dendritic cellderived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood 111: 1797–1804PubMedCrossRefGoogle Scholar
  7. 7.
    Delcuve GP, Rastegar M, Davie JR (2009) Epigenetic control. J Cell Physiol 219: 243-250 8. Fisher AG (2002) Cellular identity and lineage choice. Nat Rev Immunol 2: 977–982Google Scholar
  8. 9.
    Smale ST, Fisher AG (2002) Chromatin structure and gene regulation in the immune system. Annu Rev Immunol 20: 427–462PubMedCrossRefGoogle Scholar
  9. 10.
    Patel DR, Richardson BC (2010) Epigenetic mechanisms in lupus. Curr Opin Rheumatol 22: 478–482PubMedCrossRefGoogle Scholar
  10. 11.
    Carson WF, Cavassani KA, Dou Y, Kunkel SL (2011) Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics 6: 273–283PubMedCrossRefGoogle Scholar
  11. 12.
    Wang H, Ma S (2008) The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med 26: 711–715PubMedCrossRefGoogle Scholar
  12. 13.
    Oberholzer A, Oberholzer C, Moldawer LL (2001) Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 16: 83–96PubMedCrossRefGoogle Scholar
  13. 14.
    Kox WJ, Volk T, Kox SN, Volk HD (2000) Immunomodulatory therapies in sepsis. Intensive Care Med 26 (Suppl 1):S124–128PubMedCrossRefGoogle Scholar
  14. 15.
    Ward NS, Casserly B, Ayala A (2008) The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med 29: 617–625PubMedCrossRefGoogle Scholar
  15. 16.
    Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M (2010) Immunosuppression following surgical and traumatic injury. Surg Today 40: 793–808PubMedCrossRefGoogle Scholar
  16. 17.
    Wen H, Hogaboam CM, Gauldie J, Kunkel SL (2006) Severe sepsis exacerbates cell-mediated immunity in the lung due to an altered dendritic cell cytokine profile. Am J Pathol 168: 1940–1950PubMedCrossRefGoogle Scholar
  17. 18.
    Lyn-Kew K, Rich E, Zeng X, et al (2010) IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PLoS One 5:e11145PubMedCrossRefGoogle Scholar
  18. 19.
    Carson WF, Cavassani KA, Ito T, et al (2010) Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis. Eur J Immunol 40: 998–1010PubMedCrossRefGoogle Scholar
  19. 20.
    Cavassani KA, Carson WF 4th, Moreira AP, et al (2010) The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood 115: 4403–4411PubMedCrossRefGoogle Scholar
  20. 21.
    Fujihara M, Muroi M, Tanamoto K, et al (2003) Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol Ther 100: 171–194PubMedCrossRefGoogle Scholar
  21. 22.
    Chan C, Li L, McCall CE, Yoza BK (2005) Endotoxin tolerance disrupts chromatin remodeling and NF-kappaB transactivation at the IL-1beta promoter. J Immunol 175: 461–468PubMedGoogle Scholar
  22. 23.
    El Gazzar M, Yoza BK, Chen X, et al (2008) G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J Biol Chem 283: 32198–32208PubMedCrossRefGoogle Scholar
  23. 24.
    Trinchieri G (2003) zInterleukin-12 and the regulation of innate resistance and adaptive immunity}. Nat Rev Immunol 3: 133–146PubMedCrossRefGoogle Scholar
  24. 25.
    Kasten KR, Tschop J, Adediran SG, Hildeman DA, Caldwell CC (2010) T cells are potent early mediators of the host response to sepsis. Shock 34: 327–336PubMedCrossRefGoogle Scholar
  25. 26.
    Miller AC, Rashid RM, Elamin EM (2007) The “T” in trauma: the helper T-cell response and the role of immunomodulation in trauma and burn patients. J Trauma 63: 1407–1417PubMedCrossRefGoogle Scholar
  26. 27.
    Venet F, Chung CS, Kherouf H, et al (2009) Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (−)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med 35: 678–686PubMedCrossRefGoogle Scholar
  27. 28.
    Heidecke CD, Hensler T, Weighardt H, et al (1999) Selective defects of T lymphocyte function in patients with lethal intraabdominal infection. Am J Surg 178: 288–292PubMedCrossRefGoogle Scholar
  28. 29.
    Oberholzer C, Oberholzer A, Clare-Salzler M, Moldawer LL (2001) Apoptosis in sepsis: a new target for therapeutic exploration. FASEB J 15: 879–892PubMedCrossRefGoogle Scholar
  29. 30.
    Mack VE, McCarter MD, Naama HA, Calvano SE, Daly JM (1996) Dominance of T-helper 2-type cytokines after severe injury. Arch Surg 131: 1303–1308PubMedCrossRefGoogle Scholar
  30. 31.
    Brogdon JL, Xu Y, Szabo SJ, et al (2007) Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109: 1123–1130PubMedCrossRefGoogle Scholar
  31. 32.
    Zhang L, Jin S, Wang C, Jiang R, Wan J (2010) Histone deacetylase inhibitors attenuate acute lung injury during cecal ligation and puncture-induced polymicrobial sepsis. World J Surg 34: 1676–1683PubMedCrossRefGoogle Scholar
  32. 33.
    Yamashita M, Hirahara K, Shinnakasu R, et al (2006) Crucial role of MLL for the maintenance of memory T helper type 2 cell responses. Immunity 24: 611–622PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • W. F. CarsonIV
  • S. L. Kunkel

There are no affiliations available

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