Skip to main content

Advertisement

SpringerLink
Log in

Role of cellular events in the pathophysiology of sepsis

  • Review
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Introduction

Sepsis is a dysregulated host immune response due to an uncontrolled infection. It is a leading cause of mortality in adult intensive care units globally. When the host immune response induced against a local infection fails to contain it locally, it progresses to sepsis, severe sepsis, septic shock and death.

Method

Literature survey was performed on the roles of different innate and adaptive immune cells in the development and progression of sepsis. Additionally, the effects of septic changes on reprogramming of different immune cells were also summarized to prepare the manuscript.

Findings

Scientific evidences to date suggest that the loss of balance between inflammatory and anti-inflammatory responses results in reprogramming of immune cell activities that lead to irreversible tissue damaging events and multi-organ failure during sepsis. Many surface receptors expressed on immune cells at various stages of sepsis have been suggested as biomarkers for sepsis diagnosis. Various immunomodulatory therapeutics, which could improve the functions of immune cells during sepsis, were shown to restore immunological homeostasis and improve survival in animal models of sepsis.

Conclusion

In-depth and comprehensive knowledge on the immune cell activities and their correlation with severity of sepsis will help clinicians and scientists to design effective immunomodulatory therapeutics for treating sepsis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315:801–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:2063.

    Article  CAS  PubMed  Google Scholar 

  3. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10:701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.

    Article  CAS  PubMed  Google Scholar 

  5. Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5:4–11.

    Article  PubMed  Google Scholar 

  6. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013;381:774–5.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Beale R, Reinhart K, Brunkhorst FM, Dobb G, Levy M, Martin G, et al. Promoting global research excellence in severe sepsis (PROGRESS): lessons from an international sepsis registry. Infection. 2009;37:222–32.

    Article  CAS  PubMed  Google Scholar 

  8. Bernard AM, Bernard GR. The immune response: targets for the treatment of severe sepsis. Int J Inflam. 2012;2012:697592.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008;8:776–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Reinhart K, Bauer M, Riedemann NC, Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012;25:609–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Balajthy Z, Aradi J, Balajthy Z. Molecular therapies. Debrecen: Debreceni Egyetem; 2011. p. 51–8.

  12. Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun. 2010;2:439–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.

    Article  CAS  PubMed  Google Scholar 

  14. Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC. Postinjury multiple organ failure: a bimodal phenomenon. J Trauma. 1996;40:501–10 (discussion 510–2).

    Article  CAS  PubMed  Google Scholar 

  15. Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol. 2014;15:602–11.

    Article  CAS  PubMed  Google Scholar 

  16. Lerman YV, Lim K, Hyun YM, Falkner KL, Yang H, Pietropaoli AP, et al. Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin alpha3beta1-dependent. Blood. 2014;124:3515–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sawa Y, Ueki T, Hata M, Iwasawa K, Tsuruga E, Kojima H, et al. LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium. J Histochem Cytochem. 2008;56:97–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lerman YV, Kim M. Neutrophil migration under normal and sepsis conditions. Cardiovasc Hematol Disord: Drug Targets. 2015;15:19–28.

    Article  CAS  Google Scholar 

  19. Zhang P, Xie M, Spitzer JA. Hepatic neutrophil sequestration in early sepsis: enhanced expression of adhesion molecules and phagocytic activity. Shock. 1994;2:133–40.

    Article  CAS  PubMed  Google Scholar 

  20. Kobayashi Y. The role of chemokines in neutrophil biology. Front Biosci. 2008;13:2400–7.

    Article  CAS  PubMed  Google Scholar 

  21. Hoffmeyer F, Witte K, Schmidt RE. The high-affinity Fc gamma RI on PMN: regulation of expression and signal transduction. Immunology. 1997;92:544–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Layseca-Espinosa E, Perez-Gonzalez LF, Torres-Montes A, Baranda L, de la Fuente H, Rosenstein Y, et al. Expression of CD64 as a potential marker of neonatal sepsis. Pediatr Allergy Immunol. 2002;13:319–27.

    Article  PubMed  Google Scholar 

  23. McAvoy EF, McDonald B, Parsons SA, Wong CH, Landmann R, Kubes P. The role of CD14 in neutrophil recruitment within the liver microcirculation during endotoxemia. J Immunol. 2011;186:2592–601.

    Article  CAS  PubMed  Google Scholar 

  24. Bosmann M, Ward PA. Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis. Adv Exp Med Biol. 2012;946:147–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cristofaro P, Opal SM. The Toll-like receptors and their role in septic shock. Expert Opin Ther Targets. 2003;7:603–12.

    Article  CAS  PubMed  Google Scholar 

  26. Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410:1103–7.

    Article  CAS  PubMed  Google Scholar 

  27. Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock. 2001;16:83–96.

    Article  CAS  PubMed  Google Scholar 

  28. Brown K, Brain S, Pearson J, Edgeworth J, Lewis S, Treacher D. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368:157–69.

    Article  CAS  PubMed  Google Scholar 

  29. Wagner C, Pioch M, Meyer C, Iking-Konert C, Andrassy K, Hansch GM. Differentiation of polymorphonuclear neutrophils in patients with systemic infections and chronic inflammatory diseases: evidence of prolonged life span and de novo synthesis of fibronectin. J Mol Med (Berl). 2000;78:337–45.

    Article  CAS  Google Scholar 

  30. Taneja R, Parodo J, Jia SH, Kapus A, Rotstein OD, Marshall JC. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit Care Med. 2004;32:1460–9.

    Article  CAS  PubMed  Google Scholar 

  31. Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC. Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8. J Biol Chem. 2008;283:5402–13.

    Article  CAS  PubMed  Google Scholar 

  32. Markiewski MM, DeAngelis RA, Lambris JD. Complexity of complement activation in sepsis. J Cell Mol Med. 2008;12:2245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ward PA. The dark side of C5a in sepsis. Nat Rev Immunol. 2004;4:133–42.

    Article  CAS  PubMed  Google Scholar 

  34. Albertine KH, Soulier MF, Wang Z, Ishizaka A, Hashimoto S, Zimmerman GA, et al. Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol. 2002;161:1783–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5.

    Article  CAS  PubMed  Google Scholar 

  36. Camicia G, Pozner R, de Larranaga G. Neutrophil extracellular traps in sepsis. Shock. 2014;42:286–94.

    Article  CAS  PubMed  Google Scholar 

  37. Gao X, Hao S, Yan H, Ding W, Li K, Li J. Neutrophil extracellular traps contribute to the intestine damage in endotoxemic rats. J Surg Res. 2015;195:211–8.

    Article  CAS  PubMed  Google Scholar 

  38. Hashiba M, Huq A, Tomino A, Hirakawa A, Hattori T, Miyabe H, et al. Neutrophil extracellular traps in patients with sepsis. J Surg Res. 2015;194:248–54.

    Article  CAS  PubMed  Google Scholar 

  39. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–82.

    Article  CAS  PubMed  Google Scholar 

  40. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view. Mediat Inflamm. 2013;2013:165974.

    Article  CAS  Google Scholar 

  41. Kopydlowski KM, Salkowski CA, Cody MJ, van Rooijen N, Major J, Hamilton TA, et al. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J Immunol. 1999;163:1537–44.

    CAS  PubMed  Google Scholar 

  42. Rollins BJ. Chemokines. Blood. 1997;90:909–28.

    CAS  PubMed  Google Scholar 

  43. Sha Y, Zmijewski J, Xu Z, Abraham E. HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol. 2008;180:2531–7.

    Article  CAS  PubMed  Google Scholar 

  44. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004;255:320–31.

    Article  CAS  PubMed  Google Scholar 

  45. Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock. 2006;26:174–9.

    Article  CAS  PubMed  Google Scholar 

  46. Huang X, Chen Y, Chung CS, Yuan Z, Monaghan SF, Wang F, et al. Identification of B7-H1 as a novel mediator of the innate immune/proinflammatory response as well as a possible myeloid cell prognostic biomarker in sepsis. J Immunol. 2014;192:1091–9.

    Article  CAS  PubMed  Google Scholar 

  47. Riedemann NC, Guo RF, Gao H, Sun L, Hoesel M, Hollmann TJ, et al. Regulatory role of C5a on macrophage migration inhibitory factor release from neutrophils. J Immunol. 2004;173:1355–9.

    Article  CAS  PubMed  Google Scholar 

  48. Cavaillon JM, Adib-Conquy M. Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care. 2006;10:233.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ellaban E, Bolgos G, Remick D. Selective macrophage suppression during sepsis. Cell Immunol. 2004;231:103–11.

    Article  CAS  PubMed  Google Scholar 

  50. Sen R, Smale ST. Selectivity of the NF-κB response. Cold Spring Harb Perspect Biol. 2010;2:a000257.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bergenfelz C, Medrek C, Ekstrom E, Jirstrom K, Janols H, Wullt M, et al. Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients. J Immunol. 2012;188:5448–58.

    Article  CAS  PubMed  Google Scholar 

  52. Mahajan S, Saini A, Chandra V, Nanduri R, Kalra R, Bhagyaraj E, et al. Nuclear receptor Nr4a2 promotes alternative polarization of macrophages and confer protection in sepsis. J Biol Chem. 2015;290(30):18304–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Newton S, Ding Y, Chung CS, Chen Y, Lomas-Neira JL, Ayala A. Sepsis-induced changes in macrophage co-stimulatory molecule expression: CD86 as a regulator of anti-inflammatory IL-10 response. Surg Infect (Larchmt). 2004;5:375–83.

    Article  Google Scholar 

  54. Dahdah A, Gautier G, Attout T, Fiore F, Lebourdais E, Msallam R, et al. Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis. J Clin Invest. 2014;124:4577–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Scumpia PO, McAuliffe PF, O’Malley KA, Ungaro R, Uchida T, Matsumoto T, et al. CD11c + dendritic cells are required for survival in murine polymicrobial sepsis. J Immunol. 2005;175:3282–6.

    Article  CAS  PubMed  Google Scholar 

  56. Wen H, Hogaboam CM, Gauldie J, Kunkel SL. Severe sepsis exacerbates cell-mediated immunity in the lung due to an altered dendritic cell cytokine profile. Am J Pathol. 2006;168:1940–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dreschler K, Bratke K, Petermann S, Thamm P, Kuepper M, Virchow JC, et al. Altered phenotype of blood dendritic cells in patients with acute pneumonia. Respiration. 2012;83:209–17.

    Article  CAS  PubMed  Google Scholar 

  58. Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol. 2002;168:2493–500.

    Article  CAS  PubMed  Google Scholar 

  59. Guisset O, Dilhuydy MS, Thiebaut R, Lefevre J, Camou F, Sarrat A, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med. 2007;33:148–52.

    Article  PubMed  Google Scholar 

  60. Bohannon J, Cui W, Sherwood E, Toliver-Kinsky T. Dendritic cell modification of neutrophil responses to infection after burn injury. J Immunol. 2010;185:2847–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pène F, Courtine E, Ouaaz F, Zuber B, Sauneuf B, Sirgo G, et al. Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells. Infect Immun. 2009;77:5651–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Poehlmann H, Schefold JC, Zuckermann-Becker H, Volk HD, Meisel C. Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care. 2009;13:R119.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Faivre V, Lukaszewicz AC, Alves A, Charron D, Payen D, Haziot A. Human monocytes differentiate into dendritic cells subsets that induce anergic and regulatory T cells in sepsis. PLoS ONE. 2012;7:e47209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gautier EL, Huby T, Saint-Charles F, Ouzilleau B, Chapman MJ, Lesnik P. Enhanced dendritic cell survival attenuates lipopolysaccharide-induced immunosuppression and increases resistance to lethal endotoxic shock. J Immunol. 2008;180:6941–6.

    Article  CAS  PubMed  Google Scholar 

  65. Wesche-Soldato DE, Chung CS, Lomas-Neira J, Doughty LA, Gregory SH, Ayala A. In vivo delivery of caspase-8 or Fas siRNA improves the survival of septic mice. Blood. 2005;106:2295–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chiche L, Forel JM, Thomas G, Farnarier C, Vely F, Blery M, et al. The role of natural killer cells in sepsis. J Biomed Biotechnol. 2011;2011:986491.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Sherwood ER, Enoh VT, Murphey ED, Lin CY. Mice depleted of CD8 + T and NK cells are resistant to injury caused by cecal ligation and puncture. Lab Invest. 2004;84:1655–65.

    Article  PubMed  Google Scholar 

  68. Badgwell B, Parihar R, Magro C, Dierksheide J, Russo T, Carson WE 3rd. Natural killer cells contribute to the lethality of a murine model of Escherichia coli infection. Surgery. 2002;132:205–12.

    Article  PubMed  Google Scholar 

  69. Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4 + T lymphocytes in humans. J Immunol. 2001;166:6952–63.

    Article  CAS  PubMed  Google Scholar 

  70. Zeerleder S, Hack CE, Caliezi C, van Mierlo G, Eerenberg-Belmer A, Wolbink A, et al. Activated cytotoxic T cells and NK cells in severe sepsis and septic shock and their role in multiple organ dysfunction. Clin Immunol. 2005;116:158–65.

    Article  CAS  PubMed  Google Scholar 

  71. Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, Karp CL, et al. Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe. 2009;6:503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RA, Roosnek E. Human NK cells can control CMV infection in the absence of T cells. Blood. 2008;112:914–5.

    Article  CAS  PubMed  Google Scholar 

  73. Delano MJ, Thayer T, Gabrilovich S, Kelly-Scumpia KM, Winfield RD, Scumpia PO, et al. Sepsis induces early alterations in innate immunity that impact mortality to secondary infection. J Immunol. 2011;186:195–202.

    Article  CAS  PubMed  Google Scholar 

  74. Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev. 2011;241:180–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. De AK, Kodys KM, Pellegrini J, Yeh B, Furse RK, Bankey P, et al. Induction of global anergy rather than inhibitory Th2 lymphokines mediates posttrauma T cell immunodepression. Clin Immunol. 2000;96:52–66.

    Article  CAS  PubMed  Google Scholar 

  76. Roth G, Moser B, Krenn C, Brunner M, Haisjackl M, Almer G, et al. Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance. Biochem Biophys Res Commun. 2003;308:840–6.

    Article  CAS  PubMed  Google Scholar 

  77. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pachot A, Monneret G, Voirin N, Leissner P, Venet F, Bohe J, et al. Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin Immunol. 2005;114:61–9.

    Article  CAS  PubMed  Google Scholar 

  79. Carson WF, Cavassani KA, Ito T, Schaller M, Ishii M, Dou Y, et al. Impaired CD4 + T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis. Eur J Immunol. 2010;40:998–1010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Cabrera-Perez J, Condotta SA, James BR, Kashem SW, Brincks EL, Rai D, et al. Alterations in antigen-specific naive CD4 T cell precursors after sepsis impairs their responsiveness to pathogen challenge. J Immunol. 2015;194:1609–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Guignant C, Lepape A, Huang X, Kherouf H, Denis L, Poitevin F, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care. 2011;15:R99.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88:233–40.

    Article  CAS  PubMed  Google Scholar 

  83. Gurung P, Rai D, Condotta SA, Babcock JC, Badovinac VP, Griffith TS. Immune unresponsiveness to secondary heterologous bacterial infection after sepsis induction is TRAIL dependent. J Immunol. 2011;187:2148–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tupin E, Kinjo Y, Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol. 2007;5:405–17.

    Article  CAS  PubMed  Google Scholar 

  85. Jiang H, Chess L. An integrated view of suppressor T cell subsets in immunoregulation. J Clin Investig. 2004;114:1198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Emoto M, Miyamoto M, Yoshizawa I, Emoto Y, Schaible UE, Kita E, et al. Critical role of NK cells rather than Vα14 + NKT cells in lipopolysaccharide-induced lethal shock in mice. J Immunol. 2002;169:1426–32.

    Article  CAS  PubMed  Google Scholar 

  87. Tsujimoto H, Ono S, Matsumoto A, Kawabata T, Kinoshita M, Majima T, et al. A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells. J Hepatol. 2006;45:836–43.

    Article  CAS  PubMed  Google Scholar 

  88. Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013;93:329–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Palmer JL, Tulley JM, Kovacs EJ, Gamelli RL, Taniguchi M, Faunce DE. Injury-induced suppression of effector T cell immunity requires CD1d-positive APCs and CD1d-restricted NKT cells. J Immunol. 2006;177:92–9.

    Article  CAS  PubMed  Google Scholar 

  90. Scott MJ, Hoth JJ, Turina M, Woods DR, Cheadle WG. Interleukin-10 suppresses natural killer cell but not natural killer T cell activation during bacterial infection. Cytokine. 2006;33:79–86.

    Article  CAS  PubMed  Google Scholar 

  91. Rhee RJ, Carlton S, Lomas JL, Lane C, Brossay L, Cioffi WG, et al. Inhibition of CD1d activation suppresses septic mortality: a role for NK-T cells in septic immune dysfunction. J Surg Res. 2003;115:74–81.

    Article  CAS  PubMed  Google Scholar 

  92. Li L, Huang L, Sun-sang JS, Lobo PI, Brown MG, Gregg RK, et al. NKT cell activation mediates neutrophil IFN-γ production and renal ischemia-reperfusion injury. J Immunol. 2007;178:5899–911.

    Article  CAS  PubMed  Google Scholar 

  93. Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol. 2002;2:336–45.

    Article  CAS  PubMed  Google Scholar 

  94. Hedges JF, Lubick KJ, Jutila MA. Gamma delta T cells respond directly to pathogen-associated molecular patterns. J Immunol. 2005;174:6045–53.

    Article  CAS  PubMed  Google Scholar 

  95. Jameson J, Witherden D, Havran WL. T-cell effector mechanisms: gammadelta and CD1d-restricted subsets. Curr Opin Immunol. 2003;15:349–53.

    Article  CAS  PubMed  Google Scholar 

  96. Schwacha MG, Ayala A, Chaudry IH. Insights into the role of gammadelta T lymphocytes in the immunopathogenic response to thermal injury. J Leukoc Biol. 2000;67:644–50.

    CAS  PubMed  Google Scholar 

  97. Daniel T, Thobe BM, Chaudry IH, Choudhry MA, Hubbard WJ, Schwacha MG. Regulation of the postburn wound inflammatory response by gammadelta T-cells. Shock. 2007;28:278–83.

    Article  CAS  PubMed  Google Scholar 

  98. Alexander M, Daniel T, Chaudry IH, Choudhry MA, Schwacha MG. T cells of the gammadelta T-cell receptor lineage play an important role in the postburn wound healing process. J Burn Care Res. 2006;27:18–25.

    Article  PubMed  Google Scholar 

  99. Hirsh M, Dyugovskaya L, Kaplan V, Krausz MM. Response of lung gammadelta T cells to experimental sepsis in mice. Immunology. 2004;112:153–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chung CS, Watkins L, Funches A, Lomas-Neira J, Cioffi WG, Ayala A. Deficiency of gammadelta T lymphocytes contributes to mortality and immunosuppression in sepsis. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1338–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Enoh VT, Lin SH, Lin CY, Toliver-Kinsky T, Murphey ED, Varma TK, et al. Mice depleted of alphabeta but not gammadelta T cells are resistant to mortality caused by cecal ligation and puncture. Shock. 2007;27:507–19.

    Article  CAS  PubMed  Google Scholar 

  102. Matsushima A, Ogura H, Fujita K, Koh T, Tanaka H, Sumi Y, et al. Early activation of gammadelta T lymphocytes in patients with severe systemic inflammatory response syndrome. Shock. 2004;22:11–5.

    Article  CAS  PubMed  Google Scholar 

  103. Venet F, Bohe J, Debard AL, Bienvenu J, Lepape A, Monneret G. Both percentage of gammadelta T lymphocytes and CD3 expression are reduced during septic shock. Crit Care Med. 2005;33:2836–40.

    Article  CAS  PubMed  Google Scholar 

  104. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7:875–88.

    Article  CAS  PubMed  Google Scholar 

  105. MacConmara MP, Maung AA, Fujimi S, McKenna AM, Delisle A, Lapchak PH, et al. Increased CD4 + CD25 + T regulatory cell activity in trauma patients depresses protective Th1 immunity. Ann Surg. 2006;244:514–23.

    PubMed  PubMed Central  Google Scholar 

  106. Scumpia PO, Delano MJ, Kelly KM, O’Malley KA, Efron PA, McAuliffe PF, et al. Increased natural CD4 + CD25 + regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol. 2006;177:7943–9.

    Article  CAS  PubMed  Google Scholar 

  107. Wisnoski N, Chung CS, Chen Y, Huang X, Ayala A. The contribution of CD4 + CD25 + T-regulatory-cells to immune suppression in sepsis. Shock. 2007;27:251–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chen X, Baumel M, Mannel DN, Howard OM, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4 + CD25 + T regulatory cells. J Immunol. 2007;179:154–61.

    Article  CAS  PubMed  Google Scholar 

  109. Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol. 2005;78:325–37.

    Article  CAS  PubMed  Google Scholar 

  110. Tang L, Bai J, Chung CS, Lomas-Neira J, Chen Y, Huang X, et al. Programmed cell death receptor ligand 1 modulates the regulatory T cells’ capacity to repress shock/sepsis-induced indirect acute lung injury by recruiting phosphatase SRC homology region 2 domain-containing phosphatase 1. Shock. 2015;43:47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Molinaro R, Pecli C, Guilherme RF, Alves-Filho JC, Cunha FQ, Canetti C, et al. CCR4 controls the suppressive effects of regulatory T cells on early and late events during severe sepsis. PLoS ONE. 2015;10:e0133227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Bermejo-Martin JF, Andaluz-Ojeda D, Almansa R, Gandia F, Gomez-Herreras JI, Gomez-Sanchez E, et al. Defining immunological dysfunction in sepsis: a requisite tool for precision medicine. J Infect. 2016;72:525–36.

    Article  PubMed  Google Scholar 

  113. Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol. 2010;10:778–86.

    Article  CAS  PubMed  Google Scholar 

  114. Quartier P, Potter PK, Ehrenstein MR, Walport MJ, Botto M. Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur J Immunol. 2005;35:252–60.

    Article  CAS  PubMed  Google Scholar 

  115. Kelly-Scumpia KM, Scumpia PO, Weinstein JS, Delano MJ, Cuenca AG, Nacionales DC, et al. B cells enhance early innate immune responses during bacterial sepsis. J Exp Med. 2011;208:1673–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012;335:597–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Monserrat J, de Pablo R, Diaz-Martin D, Rodriguez-Zapata M, de la Hera A, Prieto A, et al. Early alterations of B cells in patients with septic shock. Crit Care. 2013;17:R105.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, et al. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276:404–12.

    Article  CAS  PubMed  Google Scholar 

  119. van der Poll T. Immunotherapy of sepsis. Lancet Infect Dis. 2001;1:165–74.

    Article  PubMed  Google Scholar 

  120. Sarangi PP, Hyun YM, Lerman YV, Pietropaoli AP, Kim M. Role of beta1 integrin in tissue homing of neutrophils during sepsis. Shock. 2012;38:281–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Elphick GF, Sarangi PP, Hyun YM, Hollenbaugh JA, Ayala A, Biffl WL, et al. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood. 2009;113:4078–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hutchins NA, Unsinger J, Hotchkiss RS, Ayala A. The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med. 2014;20:224–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34:556–63.

    Article  CAS  PubMed  Google Scholar 

  125. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Laudanski K, Miller-Graziano C, Xiao W, Mindrinos MN, Richards DR, De A, et al. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. Proc Natl Acad Sci USA. 2006;103:15564–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA. 2009;106:6303–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K, et al. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care. 2010;14:R220.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Li WQ, Guszczynski T, Hixon JA, Durum SK. Interleukin-7 regulates Bim proapoptotic activity in peripheral T-cell survival. Mol Cell Biol. 2010;30:590–600.

    Article  PubMed  CAS  Google Scholar 

  133. Sportes C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205:1701–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Morre M, Beq S. Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival. Target Oncol. 2012;7:55–68.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Lu J, Giuntoli RL 2nd, Omiya R, Kobayashi H, Kennedy R, Celis E. Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes. Clin Cancer Res. 2002;8:3877–84.

    CAS  PubMed  Google Scholar 

  136. Inoue S, Unsinger J, Davis CG, Muenzer JT, Ferguson TA, Chang K, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol. 2010;184:1401–9.

    Article  CAS  PubMed  Google Scholar 

  137. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640–8.

    Article  CAS  PubMed  Google Scholar 

  138. Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ferguson NR, Galley HF, Webster NR. T helper cell subset ratios in patients with severe sepsis. Intensive Care Med. 1999;25:106–9.

    Article  CAS  PubMed  Google Scholar 

  140. Flohe SB, Agrawal H, Flohe S, Rani M, Bangen JM, Schade FU. Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med. 2008;14:247–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012;186:838–45.

    Article  CAS  PubMed  Google Scholar 

  142. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11:597–610.

    CAS  PubMed  Google Scholar 

  143. Essandoh K, Fan GC. Role of extracellular and intracellular microRNAs in sepsis. Biochim Biophys Acta. 2014;1842:2155–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Shankar-Hari M, Lord GM. How might a diagnostic microRNA signature be used to speed up the diagnosis of sepsis? Expert Rev Mol Diagn. 2014;14:249–51.

    Article  CAS  PubMed  Google Scholar 

  145. Tacke F, Roderburg C, Benz F, Cardenas DV, Luedde M, Hippe HJ, et al. Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients. Crit Care Med. 2014;42:1096–104.

    Article  CAS  PubMed  Google Scholar 

  146. Ma Y, Vilanova D, Atalar K, Delfour O, Edgeworth J, Ostermann M, et al. Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis. PLoS ONE. 2013;8:e75918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie L. Serum microRNA signatures identified by Solexa sequencing predict sepsis patients’ mortality: a prospective observational study. PLoS ONE. 2012;7:e38885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dorhoi A, Iannaccone M, Farinacci M, Fae KC, Schreiber J, Moura-Alves P, et al. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J Clin Invest. 2013;123:4836–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, Gasperini S, et al. IL-10-induced microRNA-187 negatively regulates TNF-alpha, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci USA. 2012;109:E3101–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Moon HG, Yang J, Zheng Y, Jin Y. miR-15a/16 regulates macrophage phagocytosis after bacterial infection. J Immunol. 2014;193:4558–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Yekebas EF, Eisenberger CF, Ohnesorge H, Saalmuller A, Elsner HA, Engelhardt M, et al. Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis. Crit Care Med. 2001;29:1423–30.

    Article  CAS  PubMed  Google Scholar 

  152. Kumagai T, Takeyama N, Yabuki T, Harada M, Miki Y, Kanou H, et al. Apheresis of activated leukocytes with an immobilized polymyxin B filter in patients with septic shock. Shock. 2010;34:461–6.

    Article  CAS  PubMed  Google Scholar 

  153. Reilly D, Taylor MA, Beattie NG, Campbell JH, McSharry C, Aitchison TC, et al. Is evidence for homoeopathy reproducible? Lancet. 1994;344:1601–6.

    Article  CAS  PubMed  Google Scholar 

  154. Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet. 1997;350:834–43.

    Article  CAS  PubMed  Google Scholar 

  155. Frass M, Linkesch M, Banyai S, Resch G, Dielacher C, Lobl T, et al. Adjunctive homeopathic treatment in patients with severe sepsis: a randomized, double-blind, placebo-controlled trial in an intensive care unit. 2005. Homeopathy. 2011;100:95–100.

    Article  CAS  PubMed  Google Scholar 

  156. Da Rocha Piemonte M, De Freitas Buchi D. Analysis of IL-2, IFN-gamma and TNF-alpha production, alpha5 beta1 integrins and actin filaments distribution in peritoneal mouse macrophages treated with homeopathic medicament. J Submicrosc Cytol Pathol. 2002;34:255–63.

    CAS  PubMed  Google Scholar 

  157. Erhard M, Kellner J, Wild J, Lösch U, Hatiboglu FS. Effect of echinacea, aconitum, lachesis and apis extracts, and their combinations on phagocytosis of human granulocytes. Phytotherapy Research. 1994;8:14–7.

    Article  Google Scholar 

Download references

Acknowledgments

We thank the Department of Biotechnology, Govt. of India for funding (102/IFD/SAN/1671/2014-2015-P.P.S.). C.B., P.D., and P.C. are supported by University Grant Commission (UGC), Indian Council of Medical Research (ICMR), and Ministry of Human Resource Development (MHRD), Govt. of India, respectively. We thank Dr. Kiran Ambatipudi for critical reading of the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India

      Chandra Bhan, Pankaj Dipankar, Papiya Chakraborty & Pranita P. Sarangi

    Authors
    1. Chandra Bhan
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Pankaj Dipankar
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Papiya Chakraborty
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Pranita P. Sarangi
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Pranita P. Sarangi.

    Ethics declarations

    Conflict of interest

    The author(s) confirm that this article content has no conflict of interest.

    Additional information

    Responsible Editor: Artur Bauhofer.

    C. Bhan, P. Dipankar and P. Chakraborty have contributed equally to the work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Bhan, C., Dipankar, P., Chakraborty, P. et al. Role of cellular events in the pathophysiology of sepsis. Inflamm. Res. 65, 853–868 (2016). https://doi.org/10.1007/s00011-016-0970-x

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00011-016-0970-x

    Keywords

    Search

    Navigation