Skip to main content

Advertisement

SpringerLink
Log in

Cytokine storm and sepsis disease pathogenesis

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Infectious diseases are a leading cause of death worldwide. Sepsis is a severe clinical syndrome related to the host response to infection. The severity of infections is due to an activation cascade that will lead to an autoamplifying cytokine production: the cytokine storm. Cytokines are a broad category of relatively small proteins (<40 kDa) that are produced and released with the aim of cell signaling. Our understanding of the processes that trigger this tremendous amount of cytokine production has made dramatic progress over the last decades, but unfortunately, these findings could not translate yet into effective treatments; so far, all clinical trials targeting cytokine production or effects failed. This review aims to summarize the pathophysiology of the cytokine storm; to describe the type, effects, and kinetics of cytokine production; and to discuss the therapeutic challenges of targeting cytokines. New promising therapeutic strategies focusing on the endothelium, as a source and a target of cytokines, are described.

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

Similar content being viewed by others

References

  1. Ferrara JL, Abhyankar S, Gilliland DG (1993) Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc 25(1 Pt 2):1216–1217

    CAS  PubMed  Google Scholar 

  2. Yokota S (2003) Influenza-associated encephalopathy—pathophysiology and disease mechanisms. Nihon Rinsho 61(11):1953–1958

    PubMed  Google Scholar 

  3. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG (2012) Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76(1):16–32. doi:10.1128/MMBR.05015-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bone RC, Sibbald WJ, Sprung CL (1992) The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 101(6):1481–1483

    Article  CAS  PubMed  Google Scholar 

  5. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810. doi:10.1001/jama.2016.0287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K, International Forum of Acute Care T (2016) Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 193(3):259–272. doi:10.1164/rccm.201504-0781OC

    Article  CAS  PubMed  Google Scholar 

  7. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS (2010) Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 362(23):2155–2165. doi:10.1056/NEJMoa0908610

    Article  CAS  PubMed  Google Scholar 

  8. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29. doi:10.3322/caac.21208

    Article  PubMed  Google Scholar 

  9. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD (2010) Critical care and the global burden of critical illness in adults. Lancet 376(9749):1339–1346. doi:10.1016/S0140-6736(10)60446-1

    Article  PubMed  Google Scholar 

  10. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216. doi:10.1146/annurev.immunol.20.083001.084359

    Article  CAS  PubMed  Google Scholar 

  11. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124(4):783–801. doi:10.1016/j.cell.2006.02.015

    Article  CAS  PubMed  Google Scholar 

  12. Netea MG (2013) Training innate immunity: the changing concept of immunological memory in innate host defence. Eur J Clin Investig 43(8):881–884. doi:10.1111/eci.12132

    Article  CAS  Google Scholar 

  13. Netea MG, Quintin J, van der Meer JW (2011) Trained immunity: a memory for innate host defense. Cell Host Microbe 9(5):355–361. doi:10.1016/j.chom.2011.04.006

    Article  CAS  PubMed  Google Scholar 

  14. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86(6):973–983

    Article  CAS  PubMed  Google Scholar 

  15. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388(6640):394–397. doi:10.1038/41131

    Article  CAS  PubMed  Google Scholar 

  16. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085–2088

    Article  CAS  PubMed  Google Scholar 

  17. Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, Birdwell D, Alejos E, Silva M, Du X, Thompson P, Chan EK, Ledesma J, Roe B, Clifton S, Vogel SN, Beutler B (1998) Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis 24(3):340–355

    Article  CAS  PubMed  Google Scholar 

  18. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650. doi:10.1016/j.immuni.2011.05.006

    Article  CAS  PubMed  Google Scholar 

  19. Gao H, Leaver SK, Burke-Gaffney A, Finney SJ (2008) Severe sepsis and Toll-like receptors. Semin Immunopathol 30(1):29–40. doi:10.1007/s00281-007-0101-4

    Article  CAS  PubMed  Google Scholar 

  20. Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365(9453):63–78. doi:10.1016/S0140-6736(04)17667-8

    Article  CAS  PubMed  Google Scholar 

  21. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4(7):499–511. doi:10.1038/nri1391

    Article  CAS  PubMed  Google Scholar 

  22. Armstrong L, Medford AR, Hunter KJ, Uppington KM, Millar AB (2004) Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol 136(2):312–319. doi:10.1111/j.1365-2249.2004.02433.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Harter L, Mica L, Stocker R, Trentz O, Keel M (2004) Increased expression of toll-like receptor-2 and -4 on leukocytes from patients with sepsis. Shock 22(5):403–409

    Article  PubMed  CAS  Google Scholar 

  24. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7(1):31–40. doi:10.1038/nri1997

    Article  CAS  PubMed  Google Scholar 

  25. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR (2006) The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7(3):318–325. doi:10.1038/ni1305

    Article  CAS  PubMed  Google Scholar 

  26. Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S (2003) Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 197(9):1119–1124. doi:10.1084/jem.20021890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brown GD, Taylor PR, Reid DM, Willment JA, Williams DL, Martinez-Pomares L, Wong SY, Gordon S (2002) Dectin-1 is a major beta-glucan receptor on macrophages. J Exp Med 196(3):407–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, Forster I, Ruland J (2006) Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442(7103):651–656. doi:10.1038/nature04926

    Article  CAS  PubMed  Google Scholar 

  29. Brown GD, Gordon S (2001) Immune recognition. A new receptor for beta-glucans. Nature 413(6851):36–37. doi:10.1038/35092620

    Article  CAS  PubMed  Google Scholar 

  30. Dennehy KM, Brown GD (2007) The role of the beta-glucan receptor Dectin-1 in control of fungal infection. J Leukoc Biol 82(2):253–258. doi:10.1189/jlb.1206753

    Article  CAS  PubMed  Google Scholar 

  31. den Dunnen J, Gringhuis SI, Geijtenbeek TB (2009) Innate signaling by the C-type lectin DC-SIGN dictates immune responses. Cancer Immunol, Immunother 58(7):1149–1157. doi:10.1007/s00262-008-0615-1

    Article  CAS  Google Scholar 

  32. Fitzgerald ME, Rawling DC, Vela A, Pyle AM (2014) An evolving arsenal: viral RNA detection by RIG-I-like receptors. Curr Opin Microbiol 20:76–81. doi:10.1016/j.mib.2014.05.004

    Article  CAS  PubMed  Google Scholar 

  33. Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101(10):3765–3777. doi:10.1182/blood-2002-06-1887

    Article  CAS  PubMed  Google Scholar 

  34. Ince C, Mayeux PR, Nguyen T, Gomez H, Kellum JA, Ospina-Tascon GA, Hernandez G, Murray P, De Backer D, Workgroup AX (2016) The endothelium in sepsis. Shock 45(3):259–270. doi:10.1097/SHK.0000000000000473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vallet B (2003) Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction? Crit Care 7(2):130–138

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sutherland AM, Walley KR (2009) Bench-to-bedside review: association of genetic variation with sepsis. Crit Care 13(2):210. doi:10.1186/cc7702

    Article  PubMed  PubMed Central  Google Scholar 

  37. Arcaroli J, Fessler MB, Abraham E (2005) Genetic polymorphisms and sepsis. Shock 24(4):300–312

    Article  CAS  PubMed  Google Scholar 

  38. Texereau J, Pene F, Chiche JD, Rousseau C, Mira JP (2004) Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis. Crit Care Med 32(5 Suppl):S313–S319

    Article  PubMed  Google Scholar 

  39. Chung LP, Waterer GW (2011) Genetic predisposition to respiratory infection and sepsis. Crit Rev Clin Lab Sci 48(5–6):250–268. doi:10.3109/10408363.2011.641517

    Article  CAS  PubMed  Google Scholar 

  40. Cornell TT, Wynn J, Shanley TP, Wheeler DS, Wong HR (2010) Mechanisms and regulation of the gene-expression response to sepsis. Pediatrics 125(6):1248–1258. doi:10.1542/peds.2009-3274

    Article  PubMed  PubMed Central  Google Scholar 

  41. Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riche F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF (1999) Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 282(6):561–568

    Article  CAS  PubMed  Google Scholar 

  42. Calvano JE, Um JY, Agnese DM, Hahm SJ, Kumar A, Coyle SM, Calvano SE, Lowry SF (2003) Influence of the TNF-alpha and TNF-beta polymorphisms upon infectious risk and outcome in surgical intensive care patients. Surg Infect 4(2):163–169. doi:10.1089/109629603766956951

    Article  Google Scholar 

  43. Witkin SS, Gerber S, Ledger WJ (2002) Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 34(2):204–209. doi:10.1086/338261

    Article  CAS  PubMed  Google Scholar 

  44. Arnalich F, Lopez-Maderuelo D, Codoceo R, Lopez J, Solis-Garrido LM, Capiscol C, Fernandez-Capitan C, Madero R, Montiel C (2002) Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol 127(2):331–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Meyer NJ, Ferguson JF, Feng R, Wang F, Patel PN, Li M, Xue C, Qu L, Liu Y, Boyd JH, Russell JA, Christie JD, Walley KR, Reilly MP (2014) A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock. Am J Respir Crit Care Med 190(6):656–664. doi:10.1164/rccm.201403-0586OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Surbatovic M, Grujic K, Cikota B, Jevtic M, Filipovic N, Romic P, Strelic N, Magic Z (2010) Polymorphisms of genes encoding tumor necrosis factor-alpha, interleukin-10, cluster of differentiation-14 and interleukin-1ra in critically ill patients. J Crit Care 25(3):542 e541-548. doi:10.1016/j.jcrc.2009.12.003

    Article  PubMed  CAS  Google Scholar 

  47. Lorenz E, Mira JP, Frees KL, Schwartz DA (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162(9):1028–1032

    Article  CAS  PubMed  Google Scholar 

  48. Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, Ruzinski JT, Rona G, Black RA, Stratton S, Jarvik GP, Hajjar AM, Nickerson DA, Rieder M, Sevransky J, Maloney JP, Moss M, Martin G, Shanholtz C, Garcia JG, Gao L, Brower R, Barnes KC, Walley KR, Russell JA, Martin TR (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178(7):710–720. doi:10.1164/rccm.200803-462OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gallagher PM, Lowe G, Fitzgerald T, Bella A, Greene CM, McElvaney NG, O’Neill SJ (2003) Association of IL-10 polymorphism with severity of illness in community acquired pneumonia. Thorax 58(2):154–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Azab SF, Abdalhady MA, Elsaadany HF, Elkomi MA, Elhindawy EM, Sarhan DT, Salam MM, Allah MA, Emam AA, Noah MA, Abdelsalam NI, Abdellatif SH, Rass AA, Ismail SM, Gheith T, Aziz KA, Hamed ME, Abdelrahman HM, Ahmed AR, Nabil RM, Abdulmaksoud RS, Yousef HY (2016) Interleukin-10 -1082 G/A gene polymorphisms in Egyptian children with CAP: a case-control study. Medicine (Baltimore) 95(26):e4013. doi:10.1097/MD.0000000000004013

    Article  CAS  Google Scholar 

  51. Kolb WP, Granger GA (1968) Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin. Proc Natl Acad Sci U S A 61(4):1250–1255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ruddle NH, Waksman BH (1967) Cytotoxic effect of lymphocyte-antigen interaction in delayed hypersensitivity. Science 157(3792):1060–1062

    Article  CAS  PubMed  Google Scholar 

  53. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72(9):3666–3670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A (1985) Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316(6028):552–554

    Article  CAS  PubMed  Google Scholar 

  55. Clark IA, Cowden WB (1989) Is TNF a key to acute infectious illness? Today’s Life Sci 1:26–29

    Google Scholar 

  56. Clark IA, Virelizier JL, Carswell EA, Wood PR (1981) Possible importance of macrophage-derived mediators in acute malaria. Infect Immun 32(3):1058–1066

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Clark IA (1982) Suggested importance of monokines in pathophysiology of endotoxin shock and malaria. Klin Wochenschr 60(14):756–758

    Article  CAS  PubMed  Google Scholar 

  58. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ 3rd, Zentella A, Albert JD et al (1986) Shock and tissue injury induced by recombinant human cachectin. Science 234(4775):470–474

    Article  CAS  PubMed  Google Scholar 

  59. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330(6149):662–664. doi:10.1038/330662a0

    Article  CAS  PubMed  Google Scholar 

  60. Tracey KJ, Cerami A (1989) Cachectin/tumor necrosis factor and other cytokines in infectious disease. Curr Opin Immunol 1(3):454–461

    Article  CAS  PubMed  Google Scholar 

  61. Dinarello CA (2007) Historical insights into cytokines. Eur J Immunol 37(Suppl 1):S34–S45. doi:10.1002/eji.200737772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Weber A, Wasiliew P, Kracht M (2010) Interleukin-1 (IL-1) pathway. Sci Signal 3(105):cm1. doi:10.1126/scisignal.3105cm1

    PubMed  Google Scholar 

  63. Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A, Zanc V, Carstina D, Oltean M (2011) Multiplex cytokine profiling in patients with sepsis. APMIS 119(2):155–163. doi:10.1111/j.1600-0463.2010.02705.x

    Article  CAS  PubMed  Google Scholar 

  64. Jones SA, Scheller J, Rose-John S (2011) Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 121(9):3375–3383. doi:10.1172/JCI57158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gouel-Cheron A, Allaouchiche B, Guignant C, Davin F, Floccard B, Monneret G, AzuRea G (2012) Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma. PLoS One 7(3):e33095. doi:10.1371/journal.pone.0033095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu HP, Chen CK, Chung K, Tseng JC, Hua CC, Liu YC, Chuang DY, Yang CH (2009) Serial cytokine levels in patients with severe sepsis. Inflamm Res 58(7):385–393. doi:10.1007/s00011-009-0003-0

    Article  CAS  PubMed  Google Scholar 

  67. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC, Gen IMSI (2007) Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 167(15):1655–1663. doi:10.1001/archinte.167.15.1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Riedemann NC, Guo RF, Hollmann TJ, Gao H, Neff TA, Reuben JS, Speyer CL, Sarma JV, Wetsel RA, Zetoune FS, Ward PA (2004) Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J 18(2):370–372. doi:10.1096/fj.03-0708fje

    CAS  PubMed  Google Scholar 

  69. Riedemann NC, Neff TA, Guo RF, Bernacki KD, Laudes IJ, Sarma JV, Lambris JD, Ward PA (2003) Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol 170(1):503–507

    Article  CAS  PubMed  Google Scholar 

  70. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM (2001) The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 15(1):43–58. doi:10.1096/fj.99-1003rev

    Article  CAS  PubMed  Google Scholar 

  71. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM (1993) Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260(5107):547–549

    Article  CAS  PubMed  Google Scholar 

  72. Costa VS, Mattana TC, da Silva ME (2010) Unregulated IL-23/IL-17 immune response in autoimmune diseases. Diabetes Res Clin Pract 88(3):222–226. doi:10.1016/j.diabres.2010.03.014

    Article  CAS  PubMed  Google Scholar 

  73. Reynolds JM, Angkasekwinai P, Dong C (2010) IL-17 family member cytokines: regulation and function in innate immunity. Cytokine Growth Factor Rev 21(6):413–423. doi:10.1016/j.cytogfr.2010.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189. doi:10.1016/j.immuni.2006.01.001

    Article  CAS  PubMed  Google Scholar 

  75. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397. doi:10.1038/ni1539

    Article  CAS  PubMed  Google Scholar 

  76. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448(7152):484–487. doi:10.1038/nature05970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9(6):641–649. doi:10.1038/ni.1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75(2):163–189. doi:10.1189/jlb.0603252

    Article  CAS  PubMed  Google Scholar 

  79. Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101. doi:10.1016/S0065-2776(07)96002-2

    Article  CAS  PubMed  Google Scholar 

  80. Romero CR, Herzig DS, Etogo A, Nunez J, Mahmoudizad R, Fang G, Murphey ED, Toliver-Kinsky T, Sherwood ER (2010) The role of interferon-gamma in the pathogenesis of acute intra-abdominal sepsis. J Leukoc Biol 88(4):725–735. doi:10.1189/jlb.0509307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ono S, Ueno C, Aosasa S, Tsujimoto H, Seki S, Mochizuki H (2001) Severe sepsis induces deficient interferon-gamma and interleukin-12 production, but interleukin-12 therapy improves survival in peritonitis. Am J Surg 182(5):491–497

    Article  CAS  PubMed  Google Scholar 

  82. Cai S, Batra S, Lira SA, Kolls JK, Jeyaseelan S (2010) CXCL1 regulates pulmonary host defense to Klebsiella infection via CXCL2, CXCL5, NF-kappaB, and MAPKs. J Immunol 185(10):6214–6225. doi:10.4049/jimmunol.0903843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Robben PM, LaRegina M, Kuziel WA, Sibley LD (2005) Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis. J Exp Med 201(11):1761–1769. doi:10.1084/jem.20050054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD, Jaeger M, Green NM, Masedunskas A, Weigert R, Mikelis C, Wan W, Lee CC, Lim JK, Rivollier A, Yang JC, Laird GM, Wheeler RT, Alexander BD, Perfect JR, Gao JL, Kullberg BJ, Netea MG, Murphy PM (2013) CX3CR1-dependent renal macrophage survival promotes Candida control and host survival. J Clin Invest 123(12):5035–5051. doi:10.1172/JCI71307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chousterman BG, Boissonnas A, Poupel L, Baudesson de Chanville C, Adam J, Tabibzadeh N, Licata F, Lukaszewicz AC, Lombes A, Deterre P, Payen D, Combadiere C (2016) Ly6Chigh monocytes protect against kidney damage during sepsis via a CX3CR1-dependent adhesion mechanism. J Am Soc Nephrol 27(3):792–803. doi:10.1681/ASN.2015010009

    Article  CAS  PubMed  Google Scholar 

  86. Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8(7):533–544. doi:10.1038/nri2356

    Article  CAS  PubMed  Google Scholar 

  87. Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I, Tiglao E, Figueiredo JL, Iwamoto Y, Theurl I, Gorbatov R, Waring MT, Chicoine AT, Mouded M, Pittet MJ, Nahrendorf M, Weissleder R, Swirski FK (2012) Innate response activator B cells protect against microbial sepsis. Science 335(6068):597–601. doi:10.1126/science.1215173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schreuder H, Tardif C, Trump-Kallmeyer S, Soffientini A, Sarubbi E, Akeson A, Bowlin T, Yanofsky S, Barrett RW (1997) A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist. Nature 386(6621):194–200. doi:10.1038/386194a0

    Article  CAS  PubMed  Google Scholar 

  89. Dinarello CA (1997) Induction of interleukin-1 and interleukin-1 receptor antagonist. Semin Oncol 24(3 Suppl 9):S9-81–S89-93

    Google Scholar 

  90. Alexander HR, Doherty GM, Venzon DJ, Merino MJ, Fraker DL, Norton JA (1992) Recombinant interleukin-1 receptor antagonist (IL-1ra): effective therapy against gram-negative sepsis in rats. Surgery 112(2):188–193 discussion 193-184

    CAS  PubMed  Google Scholar 

  91. Herold S, Tabar TS, Janssen H, Hoegner K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmueller M, Lohmeyer J (2011) Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183(10):1380–1390. doi:10.1164/rccm.201009-1431OC

    Article  CAS  PubMed  Google Scholar 

  92. Wynn TA (2015) Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol 15(5):271–282. doi:10.1038/nri3831

    Article  CAS  PubMed  Google Scholar 

  93. Luzina IG, Keegan AD, Heller NM, Rook GA, Shea-Donohue T, Atamas SP (2012) Regulation of inflammation by interleukin-4: a review of “alternatives”. J Leukoc Biol 92(4):753–764. doi:10.1189/jlb.0412214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180(9):5771–5777

    Article  CAS  PubMed  Google Scholar 

  95. Opal SM, DePalo VA (2000) Anti-inflammatory cytokines. Chest 117(4):1162–1172

    Article  CAS  PubMed  Google Scholar 

  96. Hotchkiss RS, Monneret G, Payen D (2013) Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13(12):862–874. doi:10.1038/nri3552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG et al (1986) Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell 47(1):3–10

    Article  CAS  PubMed  Google Scholar 

  98. Weber GF, Chousterman BG, He S, Fenn AM, Nairz M, Anzai A, Brenner T, Uhle F, Iwamoto Y, Robbins CS, Noiret L, Maier SL, Zonnchen T, Rahbari NN, Scholch S, Klotzsche-von Ameln A, Chavakis T, Weitz J, Hofer S, Weigand MA, Nahrendorf M, Weissleder R, Swirski FK (2015) Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347(6227):1260–1265. doi:10.1126/science.aaa4268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bentzer P, Fjell C, Walley KR, Boyd J, Russell JA (2016) Plasma cytokine levels predict response to corticosteroids in septic shock. Intensive Care Med 42(12):1970–1979. doi:10.1007/s00134-016-4338-z

    Article  CAS  PubMed  Google Scholar 

  100. Copeland S, Warren HS, Lowry SF, Calvano SE, Remick D, Inflammation, the Host Response to Injury I (2005) Acute inflammatory response to endotoxin in mice and humans. Clin Diagn Lab Immunol 12(1):60–67. doi:10.1128/CDLI.12.1.60-67.2005

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bahador M, Cross AS (2007) From therapy to experimental model: a hundred years of endotoxin administration to human subjects. J Endotoxin Res 13(5):251–279. doi:10.1177/0968051907085986

    Article  CAS  PubMed  Google Scholar 

  102. Dorresteijn MJ, Visser T, Cox LA, Bouw MP, Pillay J, Koenderman AH, Strengers PF, Leenen LP, van der Hoeven JG, Koenderman L, Pickkers P (2010) C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia. Crit Care Med 38(11):2139–2145. doi:10.1097/CCM.0b013e3181f17be4

    Article  CAS  PubMed  Google Scholar 

  103. van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A (1990) Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 76(12):2520–2526

    PubMed  Google Scholar 

  104. Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, Miller-Graziano C, Moldawer LL, Mindrinos MN, Davis RW, Tompkins RG, Lowry SF, Inflamm, Host Response to Injury Large Scale Collab. Res P (2005) A network-based analysis of systemic inflammation in humans. Nature 437(7061):1032–1037. doi:10.1038/nature03985

    Article  CAS  PubMed  Google Scholar 

  105. Shalova IN, Lim JY, Chittezhath M, Zinkernagel AS, Beasley F, Hernandez-Jimenez E, Toledano V, Cubillos-Zapata C, Rapisarda A, Chen J, Duan K, Yang H, Poidinger M, Melillo G, Nizet V, Arnalich F, Lopez-Collazo E, Biswas SK (2015) Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. Immunity 42(3):484–498. doi:10.1016/j.immuni.2015.02.001

    Article  CAS  PubMed  Google Scholar 

  106. Cazalis MA, Lepape A, Venet F, Frager F, Mougin B, Vallin H, Paye M, Pachot A, Monneret G (2014) Early and dynamic changes in gene expression in septic shock patients: a genome-wide approach. Intensive Care Med Exp 2(1):20. doi:10.1186/s40635-014-0020-3

    Article  PubMed  PubMed Central  Google Scholar 

  107. Payen D, Lukaszewicz AC, Belikova I, Faivre V, Gelin C, Russwurm S, Launay JM, Sevenet N (2008) Gene profiling in human blood leucocytes during recovery from septic shock. Intensive Care Med 34(8):1371–1376. doi:10.1007/s00134-008-1048-1

    Article  CAS  PubMed  Google Scholar 

  108. Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC (2014) The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*. Crit Care Med 42(7):1714–1721. doi:10.1097/CCM.0000000000000325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hahn EO, Houser HB, Rammelkamp CH Jr, Denny FW, Wannamaker LW (1951) Effect of cortisone on acute streptococcal infections and poststreptococcal complications. J Clin Invest 30(3):274–281. doi:10.1172/JCI102441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353(16):1711–1723. doi:10.1056/NEJMra050541

    Article  CAS  PubMed  Google Scholar 

  111. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaud P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288(7):862–871

    Article  CAS  PubMed  Google Scholar 

  112. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J, Group CS (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358(2):111–124. doi:10.1056/NEJMoa071366

    Article  CAS  PubMed  Google Scholar 

  113. Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M (1997) Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 25(7):1115–1124

    Article  CAS  PubMed  Google Scholar 

  114. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL, Group AS (2013) Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309(11):1154–1162. doi:10.1001/jama.2013.2194

    Article  CAS  PubMed  Google Scholar 

  115. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R et al (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 273(12):934–941

    Article  CAS  PubMed  Google Scholar 

  116. McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR (1994) Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med 121(1):1–5

    Article  CAS  PubMed  Google Scholar 

  117. Payen DM, Guilhot J, Launey Y, Lukaszewicz AC, Kaaki M, Veber B, Pottecher J, Joannes-Boyau O, Martin-Lefevre L, Jabaudon M, Mimoz O, Coudroy R, Ferrandiere M, Kipnis E, Vela C, Chevallier S, Mallat J, Robert R, Group A (2015) Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med 41(6):975–984. doi:10.1007/s00134-015-3751-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Qiu P, Cui X, Sun J, Welsh J, Natanson C, Eichacker PQ (2013) Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis. Crit Care Med 41(10):2419–2429. doi:10.1097/CCM.0b013e3182982add

    Article  CAS  PubMed  Google Scholar 

  119. Schouten M, Wiersinga WJ, Levi M, van der Poll T (2008) Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 83(3):536–545. doi:10.1189/jlb.0607373

    Article  CAS  PubMed  Google Scholar 

  120. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, Recombinant human protein CWEiSSsg (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344(10):699–709. doi:10.1056/NEJM200103083441001

    Article  CAS  PubMed  Google Scholar 

  121. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gardlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD, Group P-SS (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366(22):2055–2064. doi:10.1056/NEJMoa1202290

    Article  CAS  PubMed  Google Scholar 

  122. London NR, Zhu W, Bozza FA, Smith MC, Greif DM, Sorensen LK, Chen L, Kaminoh Y, Chan AC, Passi SF, Day CW, Barnard DL, Zimmerman GA, Krasnow MA, Li DY (2010) Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med 2(23):23ra19. doi:10.1126/scitranslmed.3000678

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Zhao H, Anand AR, Ganju RK (2014) Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. J Immunol 192(1):385–393. doi:10.4049/jimmunol.1302021

    Article  CAS  PubMed  Google Scholar 

  124. Maceyka M, Harikumar KB, Milstien S, Spiegel S (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22(1):50–60. doi:10.1016/j.tcb.2011.09.003

    Article  CAS  PubMed  Google Scholar 

  125. Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, Martinborough E, Peach R, Oldstone MB, Rosen H (2011) Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146(6):980–991. doi:10.1016/j.cell.2011.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by a public grant overseen by the French National Research Agency (ANR) (Project “CMOS,” ANR-15-CE15-0019).

Author information

Authors and Affiliations

  1. Département d’Anesthésie-Réanimation, Hôpitaux Universitaires Lariboisière–Saint-Louis, AP-HP, Paris, France

    Benjamin G. Chousterman

  2. Inserm U1160, Hôpital Saint-Louis, Paris, France

    Benjamin G. Chousterman

  3. Center for Systems Biology, Department of Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Filip K. Swirski

  4. Department of Surgery, University of Erlangen-Nürnberg, Erlangen, Germany

    Georg F. Weber

Authors
  1. Benjamin G. Chousterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Filip K. Swirski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg F. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin G. Chousterman.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

This article is a contribution to the special issue on Cytokine Storm in Infectious Diseases - Guest Editor: John Teijaro

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chousterman, B.G., Swirski, F.K. & Weber, G.F. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 39, 517–528 (2017). https://doi.org/10.1007/s00281-017-0639-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-017-0639-8

Keywords

Search

Navigation