Skip to main content

Advertisement

Log in

New fronts emerge in the influenza cytokine storm

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

Abstract

Influenza virus is a significant pathogen in humans and animals with the ability to cause extensive morbidity and mortality. Exuberant immune responses induced following infection have been described as a “cytokine storm,” associated with excessive levels of proinflammatory cytokines and widespread tissue damage. Recent studies have painted a more complex picture of cytokine networks and their contributions to clinical outcomes. While many cytokines clearly inflict immunopathology, others have non-pathological delimited roles in sending alarm signals, facilitating viral clearance, and promoting tissue repair, such as the IL-33—amphiregulin axis, which plays a key role in resolving some types of lung damage. Recent literature suggests that type 2 cytokines, traditionally thought of as not involved in anti-influenza immunity, may play an important regulatory role. Here, we discuss the diverse roles played by cytokines after influenza infection and highlight new, serene features of the cytokine storm, while highlighting the specific functions of relevant cytokines that perform unique immune functions and may have applications for influenza therapy.

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

Access this article

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. Thompson WW, Shay DK, Weintraub E et al (2004) Influenza-associated hospitalizations in the United States. JAMA 292:1333–1340. doi:10.1001/jama.292.11.1333

    Article  CAS  PubMed  Google Scholar 

  2. Dash P, Thomas PG (2014) Host Detection and the Stealthy Phenotype in Influenza Virus Infection. In: Oldstone MBA, Compans RW (eds) Influenza Pathog. Control - Vol. II. Springer International Publishing, pp 121–147

  3. Yokota S (2003) Influenza-associated encephalopathy--pathophysiology and disease mechanisms. Nihon Rinsho Jpn J Clin Med 61:1953–1958

    Google Scholar 

  4. Clark IA (2007) The advent of the cytokine storm. Immunol Cell Biol 85:271–273. doi:10.1038/sj.icb.7100062

    Article  CAS  PubMed  Google Scholar 

  5. Tisoncik JR, Korth MJ, Simmons CP et al (2012) Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76:16–32. doi:10.1128/MMBR.05015-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu Q, Zhou Y, Yang Z (2016) The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol 13:3–10. doi:10.1038/cmi.2015.74

    Article  CAS  PubMed  Google Scholar 

  7. Teijaro JR (2014) The Role of Cytokine Responses During Influenza Virus Pathogenesis and Potential Therapeutic Options. In: Oldstone MBA, Compans RW (eds) Influenza Pathog. Control - Vol. II. Springer International Publishing, pp 3–22

  8. D’Elia RV, Harrison K, Oyston PC et al (2013) Targeting the “cytokine storm” for therapeutic benefit. Clin Vaccine Immunol 20:319–327. doi:10.1128/CVI.00636-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kato H, Sato S, Yoneyama M et al (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28. doi:10.1016/j.immuni.2005.04.010

    Article  CAS  PubMed  Google Scholar 

  10. Teijaro JR, Walsh KB, Cahalan S et al (2011) Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146:980–991. doi:10.1016/j.cell.2011.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Isaacs A, Lindenmann J (1957) Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci 147:258–267

    Article  CAS  PubMed  Google Scholar 

  12. McNab F, Mayer-Barber K, Sher A et al (2015) Type I interferons in infectious disease. Nat Rev Immunol 15:87–103. doi:10.1038/nri3787

    Article  CAS  PubMed  Google Scholar 

  13. Iwasaki A, Pillai PS (2014) Innate immunity to influenza virus infection. Nat Rev Immunol 14:315–328. doi:10.1038/nri3665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ivashkiv LB, Donlin LT (2014) Regulation of type I interferon responses. Nat Rev Immunol 14:36–49. doi:10.1038/nri3581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wack A, Terczyńska-Dyla E, Hartmann R (2015) Guarding the frontiers: the biology of type III interferons. Nat Immunol 16:802–809. doi:10.1038/ni.3212

    Article  CAS  PubMed  Google Scholar 

  16. Sadler AJ, Williams BRG (2008) Interferon-inducible antiviral effectors. Nat Rev Immunol 8:559–568. doi:10.1038/nri2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Muller U, Steinhoff U, Reis LF et al (1994) Functional role of type I and type II interferons in antiviral defense. Science 264:1918–1921. doi:10.1126/science.8009221

    Article  CAS  PubMed  Google Scholar 

  18. Davidson S, Crotta S, McCabe TM, Wack A (2014) Pathogenic potential of interferon αβ in acute influenza infection. Nat Commun 5:3864. doi:10.1038/ncomms4864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rosenberger CM, Podyminogin RL, Askovich PS et al (2014) Characterization of innate responses to influenza virus infection in a novel lung type I epithelial cell model. J Gen Virol 95:350–362. doi:10.1099/vir.0.058438-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kohlmeier JE, Cookenham T, Roberts AD et al (2010) Type I interferons regulate Cytolytic activity of memory CD8+ T cells in the lung airways during respiratory virus challenge. Immunity 33:96–105. doi:10.1016/j.immuni.2010.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Koerner I, Kochs G, Kalinke U et al (2007) Protective role of Beta interferon in host defense against influenza a virus. J Virol 81:2025–2030. doi:10.1128/JVI.01718-06

    Article  CAS  PubMed  Google Scholar 

  22. Durbin JE, Fernandez-Sesma A, Lee C-K et al (2000) Type I IFN modulates innate and specific antiviral immunity. J Immunol 164:4220–4228. doi:10.4049/jimmunol.164.8.4220

    Article  CAS  PubMed  Google Scholar 

  23. Lazear HM, Nice TJ, Diamond MS (2015) Interferon-λ: immune functions at barrier surfaces and beyond. Immunity 43:15–28. doi:10.1016/j.immuni.2015.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jewell NA, Cline T, Mertz SE et al (2010) Lambda interferon is the predominant interferon induced by influenza a virus infection in vivo. J Virol 84:11515–11522. doi:10.1128/JVI.01703-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mordstein M, Kochs G, Dumoutier L et al (2008) Interferon-λ contributes to innate immunity of mice against influenza a virus but not against Hepatotropic viruses. PLoS Pathog 4:e1000151. doi:10.1371/journal.ppat.1000151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mordstein M, Neugebauer E, Ditt V et al (2010) Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol 84:5670–5677. doi:10.1128/JVI.00272-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomas PG, Dash P, Aldridge JR Jr et al (2009) The intracellular sensor NLRP3 mediates key innate and healing responses to influenza a virus via the regulation of caspase-1. Immunity 30:566–575. doi:10.1016/j.immuni.2009.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Allen IC, Scull MA, Moore CB et al (2009) The NLRP3 Inflammasome mediates in vivo innate immunity to influenza a virus through recognition of viral RNA. Immunity 30:556–565. doi:10.1016/j.immuni.2009.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Thapa RJ, Ingram JP, Ragan KB et al (2016) DAI senses influenza a virus genomic RNA and activates RIPK3-dependent cell death. Cell Host Microbe 20:674–681. doi:10.1016/j.chom.2016.09.014

    Article  CAS  PubMed  Google Scholar 

  30. Kuriakose T, Man SM, Malireddi RKS et al (2016) ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol 1:aag2045–aag2045. doi:10.1126/sciimmunol.aag2045

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schmitz N, Kurrer M, Bachmann MF, Kopf M (2005) Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol 79:6441–6448. doi:10.1128/JVI.79.10.6441-6448.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pang IK, Ichinohe T, Iwasaki A (2013) IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8+ T cell responses to influenza a virus. Nat Immunol 14:246–253. doi:10.1038/ni.2514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ichinohe T, Lee HK, Ogura Y et al (2009) Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med 206:79–87. doi:10.1084/jem.20081667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tate MD, Ong JDH, Dowling JK et al (2016) Reassessing the role of the NLRP3 inflammasome during pathogenic influenza a virus infection via temporal inhibition. Sci Rep 6:27912. doi:10.1038/srep27912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu B, Mori I, Hossain MJ et al (2004) Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity. J Gen Virol 85:423–428. doi:10.1099/vir.0.19596-0

    Article  CAS  PubMed  Google Scholar 

  36. Denton AE, Doherty PC, Turner SJ, La Gruta NL (2007) IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8+ T cells. Eur J Immunol 37:368–375. doi:10.1002/eji.200636766

    Article  CAS  PubMed  Google Scholar 

  37. Van Der Sluijs KF, Van Elden LJR, Arens R et al (2005) Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza a virus. Immunology 114:112–120. doi:10.1111/j.1365-2567.2004.02000.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lupfer C, Thomas PG, Anand PK et al (2013) Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol 14:480–488. doi:10.1038/ni.2563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sareneva T, Matikainen S, Kurimoto M, Julkunen I (1998) Influenza a virus-induced IFN-α/β and IL-18 synergistically enhance IFN-γ Gene expression in human T cells. J Immunol 160:6032–6038

    CAS  PubMed  Google Scholar 

  40. Chao Y, Kaliaperumal N, Chretien A-S et al (2014) Human plasmacytoid dendritic cells regulate IFN-α production through activation-induced splicing of IL-18Rα. J Leukoc Biol 96:1037–1046. doi:10.1189/jlb.2A0813-465RR

    Article  PubMed  CAS  Google Scholar 

  41. Aldridge JR, Moseley CE, Boltz DA et al (2009) TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci 106:5306–5311. doi:10.1073/pnas.0900655106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Veckman V, Österlund P, Fagerlund R et al (2006) TNF-α and IFN-α enhance influenza-A-virus-induced chemokine gene expression in human A549 lung epithelial cells. Virology 345:96–104. doi:10.1016/j.virol.2005.09.043

    Article  CAS  PubMed  Google Scholar 

  43. Hufford MM, Kim TS, Sun J, Braciale TJ (2014) The Effector T Cell Response to Influenza Infection. In: Oldstone MBA, Compans RW (eds) Influenza Pathog. Control - Vol. II. Springer International Publishing, pp 423–455

  44. Peiris JSM, Cheung CY, Leung CYH, Nicholls JM (2009) Innate immune responses to influenza a H5N1: friend or foe? Trends Immunol 30:574–584. doi:10.1016/j.it.2009.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cheung C, Poon L, Lau A et al (2002) Induction of proinflammatory cytokines in human macrophages by influenza a (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360:1831–1837. doi:10.1016/S0140-6736(02)11772-7

    Article  CAS  PubMed  Google Scholar 

  46. Chan M, Cheung C, Chui W et al (2005) Proinflammatory cytokine responses induced by influenza a (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6:135. doi:10.1186/1465-9921-6-135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Szretter KJ, Gangappa S, Lu X et al (2007) Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol 81:2736–2744. doi:10.1128/JVI.02336-06

    Article  CAS  PubMed  Google Scholar 

  48. Perrone LA, Szretter KJ, Katz JM et al (2010) Mice lacking both TNF and IL-1 receptors exhibit reduced lung inflammation and delay in onset of death following infection with a highly virulent H5N1 virus. J Infect Dis 202:1161–1170. doi:10.1086/656365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hussell T, Pennycook A, Openshaw PJM (2001) Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur J Immunol 31:2566–2573. doi:10.1002/1521-4141(200109)31:9<2566::AID-IMMU2566>3.0.CO;2-L

    Article  CAS  PubMed  Google Scholar 

  50. Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457. doi:10.1038/ni.3153

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Atreya R, Neurath MF (2005) Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol 28:187–195. doi:10.1385/CRIAI:28:3:187

    Article  CAS  PubMed  Google Scholar 

  53. Rincon M (2012) Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol 33:571–577. doi:10.1016/j.it.2012.07.003

    Article  CAS  PubMed  Google Scholar 

  54. Oshansky CM, Gartland AJ, Wong S-S et al (2013) Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load. Am J Respir Crit Care Med 189:449–462. doi:10.1164/rccm.201309-1616OC

    Article  CAS  Google Scholar 

  55. Kaiser L, Fritz RS, Straus SE et al (2001) Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol 64:262–268. doi:10.1002/jmv.1045

    Article  CAS  PubMed  Google Scholar 

  56. Hagau N, Slavcovici A, Gonganau DN et al (2010) Clinical aspects and cytokine response in severe H1N1 influenza a virus infection. Crit Care 14:R203. doi:10.1186/cc9324

    Article  PubMed  PubMed Central  Google Scholar 

  57. Dienz O, Rud JG, Eaton SM et al (2012) Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol 5:258–266. doi:10.1038/mi.2012.2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lauder SN, Jones E, Smart K et al (2013) Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur J Immunol 43:2613–2625. doi:10.1002/eji.201243018

    Article  CAS  PubMed  Google Scholar 

  59. Longhi MP, Wright K, Lauder SN et al (2008) Interleukin-6 is crucial for recall of influenza-specific memory CD4+ T cells. PLoS Pathog 4:e1000006. doi:10.1371/journal.ppat.1000006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Molofsky AB, Savage AK, Locksley RM (2015) Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42:1005–1019. doi:10.1016/j.immuni.2015.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Liew FY, Girard J-P, Turnquist HR (2016) Interleukin-33 in health and disease. Nat Rev Immunol 16:676–689. doi:10.1038/nri.2016.95

    Article  CAS  PubMed  Google Scholar 

  62. Martin NT, Martin MU (2016) Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol 17:122–131. doi:10.1038/ni.3370

    Article  CAS  PubMed  Google Scholar 

  63. Kakkar R, Lee RT (2008) The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 7:827–840. doi:10.1038/nrd2660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cayrol C, Girard J-P (2014) IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol 31:31–37. doi:10.1016/j.coi.2014.09.004

    Article  CAS  PubMed  Google Scholar 

  65. Peine M, Marek RM, Löhning M (2016) IL-33 in T cell differentiation, function, and immune homeostasis. Trends Immunol 37:321–333. doi:10.1016/j.it.2016.03.007

    Article  CAS  PubMed  Google Scholar 

  66. Schmitz J, Owyang A, Oldham E et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490. doi:10.1016/j.immuni.2005.09.015

    Article  CAS  PubMed  Google Scholar 

  67. Carriere V, Roussel L, Ortega N et al (2007) IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci 104:282–287. doi:10.1073/pnas.0606854104

    Article  CAS  PubMed  Google Scholar 

  68. Kearley J, Silver JS, Sanden C et al (2015) Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity 42:566–579. doi:10.1016/j.immuni.2015.02.011

    Article  CAS  PubMed  Google Scholar 

  69. Bonilla WV, Fröhlich A, Senn K et al (2012) The Alarmin interleukin-33 drives protective antiviral CD8+ T cell responses. Science 335:984–989. doi:10.1126/science.1215418

    Article  CAS  PubMed  Google Scholar 

  70. Le Goffic R, Arshad MI, Rauch M et al (2011) Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol 45:1125–1132. doi:10.1165/rcmb.2010-0516OC

    Article  CAS  PubMed  Google Scholar 

  71. Monticelli LA, Sonnenberg GF, Abt MC et al (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12:1045–1054. doi:10.1038/ni.2131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Arpaia N, Green JA, Moltedo B et al (2015) A distinct function of regulatory T cells in tissue protection. Cell 162:1078–1089. doi:10.1016/j.cell.2015.08.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386. doi:10.1038/nri1604

    Article  CAS  PubMed  Google Scholar 

  74. Billiau A, Matthys P (2009) Interferon-γ: a historical perspective. Cytokine Growth Factor Rev 20:97–113. doi:10.1016/j.cytogfr.2009.02.004

    Article  CAS  PubMed  Google Scholar 

  75. Turner SJ, Olivas E, Gutierrez A et al (2007) Disregulated influenza a virus-specific CD8+ T cell homeostasis in the absence of IFN-γ signaling. J Immunol 178:7616–7622. doi:10.4049/jimmunol.178.12.7616

    Article  CAS  PubMed  Google Scholar 

  76. Graham MB, Dalton DK, Giltinan D et al (1993) Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med 178:1725–1732. doi:10.1084/jem.178.5.1725

    Article  CAS  PubMed  Google Scholar 

  77. Baumgarth N, Kelso A (1996) In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue. J Virol 70:4411–4418

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Karupiah G, Chen J-H, Mahalingam S et al (1998) Rapid interferon γ–dependent clearance of influenza a virus and protection from consolidating pneumonitis in nitric oxide synthase 2–deficient mice. J Exp Med 188:1541–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bot A, Bot S, Bona CA (1998) Protective role of gamma interferon during the recall response to influenza virus. J Virol 72:6637–6645

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Weiss ID, Wald O, Wald H et al (2010) IFN-γ treatment at early stages of influenza virus infection protects mice from death in a NK cell-dependent manner. J Interf Cytokine Res 30:439–449. doi:10.1089/jir.2009.0084

    Article  CAS  Google Scholar 

  81. Kim TS, Braciale TJ (2009) Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8 + T cell responses. PLoS One 4:e4204. doi:10.1371/journal.pone.0004204

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. GeurtsvanKessel CH, Willart MAM, van Rijt LS et al (2008) Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells. J Exp Med 205:1621–1634. doi:10.1084/jem.20071365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Heer AK, Harris NL, Kopf M, Marsland BJ (2008) CD4+ and CD8+ T cells exhibit differential requirements for CCR7-mediated antigen transport during influenza infection. J Immunol 181:6984–6994. doi:10.4049/jimmunol.181.10.6984

    Article  CAS  PubMed  Google Scholar 

  84. Duan S, Thomas PG (2016) Balancing immune protection and immune pathology by CD8+ T-cell responses to influenza infection. Immunol Mem 25. doi:10.3389/fimmu.2016.00025

  85. Ramana CV, DeBerge MP, Kumar A et al (2015) Inflammatory impact of IFN-γ in CD8+ T cell-mediated lung injury is mediated by both Stat1-dependent and -independent pathways. Am J Physiol - Lung Cell Mol Physiol 308:L650–L657. doi:10.1152/ajplung.00360.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wiley JA, Cerwenka A, Harkema JR et al (2001) Production of interferon-γ by influenza hemagglutinin-specific CD8 effector T cells influences the development of pulmonary immunopathology. Am J Pathol 158:119–130. doi:10.1016/S0002-9440(10)63950-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hamada H, de la Garcia-Hernandez ML, Reome JB et al (2009) Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J Immunol 182:3469–3481. doi:10.4049/jimmunol.0801814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Teijaro JR, Verhoeven D, Page CA et al (2010) Memory CD4 T cells direct protective responses to influenza virus in the lungs through helper-independent mechanisms. J Virol 84:9217–9226. doi:10.1128/JVI.01069-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Teijaro JR, Turner D, Pham Q et al (2011) Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol 187:5510–5514. doi:10.4049/jimmunol.1102243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McKinstry KK, Strutt TM, Kuang Y et al (2012) Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. J Clin Invest 122:2847–2856. doi:10.1172/JCI63689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181. doi:10.1038/nri2711

    Article  CAS  PubMed  Google Scholar 

  92. Ouyang W, Rutz S, Crellin NK et al (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109. doi:10.1146/annurev-immunol-031210-101312

    Article  CAS  PubMed  Google Scholar 

  93. Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777. doi:10.4049/jimmunol.180.9.5771

    Article  CAS  PubMed  Google Scholar 

  94. McKinstry KK, Strutt TM, Buck A et al (2009) IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge. J Immunol 182:7353–7363. doi:10.4049/jimmunol.0900657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sun J, Madan R, Karp CL, Braciale TJ (2009) Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15:277–284. doi:10.1038/nm.1929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sun K, Torres L, Metzger DW (2010) A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza a virus infection. J Virol 84:5007–5014. doi:10.1128/JVI.02408-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dutta A, Huang C-T, Chen T-C et al (2015) IL-10 inhibits neuraminidase-activated TGF-β and facilitates Th1 phenotype during early phase of infection. Nat Commun 6:6374. doi:10.1038/ncomms7374

    Article  CAS  PubMed  Google Scholar 

  98. de Jong MD, Simmons CP, Thanh TT et al (2006) Fatal outcome of human influenza a (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12:1203–1207. doi:10.1038/nm1477

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Al HS et al (2009) Immunologic changes during pandemic (H1N1) China. Emerg Infect Dis J- CDC 17(6). doi:10.3201/eid1706.100643

  100. Berasain C, Avila MA (2014) Amphiregulin. Semin Cell Dev Biol 28:31–41. doi:10.1016/j.semcdb.2014.01.005

    Article  CAS  PubMed  Google Scholar 

  101. Shoyab M, Plowman GD, McDonald VL et al (1989) Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 243:1074–1076. doi:10.1126/science.2466334

    Article  CAS  PubMed  Google Scholar 

  102. Zaiss DMW, Gause WC, Osborne LC, Artis D (2015) Emerging functions of Amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42:216–226. doi:10.1016/j.immuni.2015.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Subramaniam R, Barnes PF, Fletcher K et al (2013) Protecting against post-influenza bacterial pneumonia by increasing phagocyte recruitment and ROS production. J Infect Dis. doi:10.1093/infdis/jit830

  104. Hall OJ, Limjunyawong N, Vermillion MS et al (2016) Progesterone-based therapy protects against influenza by promoting lung repair and recovery in females. PLoS Pathog 12:e1005840. doi:10.1371/journal.ppat.1005840

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Kouro T, Takatsu K (2009) IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol 21:1303–1309. doi:10.1093/intimm/dxp102

    Article  CAS  PubMed  Google Scholar 

  106. Nussbaum JC, Van Dyken SJ, von Moltke J et al (2013) Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245–248. doi:10.1038/nature12526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mukherjee M, Sehmi R, Nair P (2014) Anti-IL5 therapy for asthma and beyond. World Allergy Organ J 7:32. doi:10.1186/1939-4551-7-32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Gorski SA, Hahn YS, Braciale TJ (2013) Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog 9:e1003615. doi:10.1371/journal.ppat.1003615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chang Y-J, Kim HY, Albacker LA et al (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12:631–638. doi:10.1038/ni.2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Graham MB, Braciale VL, Braciale TJ (1994) Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med 180:1273–1282. doi:10.1084/jem.180.4.1273

    Article  CAS  PubMed  Google Scholar 

  111. La Gruta NL, Kedzierska K, Stambas J, Doherty PC (2007) A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol 85:85–92. doi:10.1038/sj.icb.7100026

    Article  PubMed  Google Scholar 

  112. Samarasinghe AE, Woolard SN, Boyd KL et al (2014) The immune profile associated with acute allergic asthma accelerates clearance of influenza virus. Immunol Cell Biol 92:449–459. doi:10.1038/icb.2013.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Samarasinghe AE, Melo RCN, Duan S et al (2017) Eosinophils promote antiviral immunity in mice infected with influenza a virus. J Immunol:1600787. doi:10.4049/jimmunol.1600787

  114. Oldstone MBA, Teijaro JR, Walsh KB, Rosen H (2013) Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection. Virology 435:92–101. doi:10.1016/j.virol.2012.09.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gonzalez-Cabrera PJ, Brown S, Studer SM, Rosen H (2014) S1P signaling: new therapies and opportunities. F1000Prime Rep. doi:10.12703/P6-109

  116. Chang DH, Bednarczyk RA, Becker ER et al (2016) Trends in U.S. hospitalizations and inpatient deaths from pneumonia and influenza, 1996–2011. Vaccine 34:486–494. doi:10.1016/j.vaccine.2015.12.003

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by HHSN272201400006C (St. Jude Center of Excellence for Influenza Research and Surveillance), R01 AI121832, and ALSAC. We apologize to any investigators whose relevant work was not included due to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul G. Thomas.

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

Guo, Xz.J., Thomas, P.G. New fronts emerge in the influenza cytokine storm. Semin Immunopathol 39, 541–550 (2017). https://doi.org/10.1007/s00281-017-0636-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-017-0636-y

Keywords

Navigation