Cytokines in Autoinflammation

  • Angela Rösen-WolffEmail author
  • Anna RubartelliEmail author


Autoinflammatory diseases represent an expanding spectrum of diseases characterized by recurrent episodes of fever and systemic inflammation, due to disorders of innate immunity. Since the concept of autoinflammation was first affirmed in 1999 to define TNF-receptor associated periodic syndrome (TRAPS), many other monogenic autoinflammatory diseases have been identified. Uncontrolled secretion of IL-1β is responsible for the many of these syndromes, as also confirmed by the dramatic clinical response to IL-1 blockade. More recently, different mechanisms have been implicated in the pathophysiology of several monogenic autoinflammatory diseases, including cell stress, dysregulation in NF-κB signaling, ubiquitination, protein folding, type I interferon production and complement activation. In this chapter, we discuss IL-1β and other members of the IL-1 family and their inhibitors involved in monogenic autoinflammatory diseases, focusing on the mechanisms underlying their secretion in health and disease. Furthermore, we describe type I interferons and their role in autoinflammation.


IL-1 family Inflammasome Caspases Gasdermin D Autoinflammatory diseases 



Adenosine deaminase


Aicardi–Goutières syndrome


Absent in melanoma 2


Associated speck-like protein containing a CARD


Cryopyrin-associated periodic syndromes


C-terminal caspase recruitment domain


cyclic GMP-AMP


cyclic GMP-AMP synthase


Cyclooxygenase type 2


DNA-dependent activator of IFN-regulatory factors


Damage-associated molecular patterns


Deficiency of IL-1Ra


Deficiency of IL-36Ra


Familial Mediterranean fever






Interferon alpha/beta receptor




IL-1 family


Type 2 phospholipase A and inducible nitric oxide synthase


Interferon stimulated gene


Macrophage activation syndrome


Melanoma differentiation associated gene 5


Natural killer


Nucleotide-binding domain leucine-rich repeat containing


Nitric oxide


Pathogen associated molecular patterns




Proteasome-associated autoinflammatory syndromes


Pyrin domain


Receptor antagonist


Regulated in development and DNA damage responses 1


Retinoic acid inducible gene I


Receptor interacting protein


Ribonuclease H2 subunits


Reactive oxygen species


Sam domain- and HD domain containing protein


STING-associated vasculopathy with onset in infancy


Suppressor of cytokine signaling


Stimulator of interferon genes


TNF-receptor associated periodic syndrome


Three prime repair exonuclease 1


  1. 1.
    Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018;281:8–27.CrossRefGoogle Scholar
  2. 2.
    Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39:1003–18.CrossRefGoogle Scholar
  3. 3.
    Carta S, Lavieri R, Rubartelli A. Different members of the IL-1 family come out in different ways: DAMPs vs. cytokines? Front Immunol. 2013;4:123.CrossRefGoogle Scholar
  4. 4.
    Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407–20.CrossRefGoogle Scholar
  5. 5.
    Afonina IS, Müller C, Martin SJ, Beyaert R. Proteolytic processing of interleukin-1 family cytokines: variations on a common theme. Immunity. 2015;42:991–1004.CrossRefGoogle Scholar
  6. 6.
    He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41:1012–21.CrossRefGoogle Scholar
  7. 7.
    Kayagaki N, Warming S, Lamkanfi M, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21.CrossRefGoogle Scholar
  8. 8.
    Ding J, Wang K, Liu W, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111–6.CrossRefGoogle Scholar
  9. 9.
    Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.CrossRefGoogle Scholar
  10. 10.
    Kovacs SB, Miao EA. Gasdermins: effectors of pyroptosis. Trends Cell Biol. 2017;9:673–84.CrossRefGoogle Scholar
  11. 11.
    Rubartelli A, Cozzolino F, Talio M, et al. A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence. EMBO J. 1990;9:1503–10.CrossRefGoogle Scholar
  12. 12.
    Sitia R, Rubartelli A. The unconventional secretion of IL-1β: handling a dangerous weapon to optimize inflammatory responses. Semin Cell Dev Biol. 2018. [Epub ahead of print].Google Scholar
  13. 13.
    Cuervo AM. Chaperone-mediated autophagy: Dice’s ‘wild’ idea about lysosomal selectivity. Nat Rev Mol Cell Biol. 2011;12:535–41.CrossRefGoogle Scholar
  14. 14.
    Zhang M, Kenny SJ, Ge L, et al. Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion. Elife. 2015;4:e11205.CrossRefGoogle Scholar
  15. 15.
    Andrei C, Dazzi C, Lotti L, et al. The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. Mol Biol Cell. 1999;10:1463–75.CrossRefGoogle Scholar
  16. 16.
    Kayagaki N, Stowe IB, Lee BL, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–71.CrossRefGoogle Scholar
  17. 17.
    Andrei C, Margiocco P, Poggi A, et al. Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: implications for inflammatory processes. Proc Natl Acad Sci U S A. 2004;101:9745–50.CrossRefGoogle Scholar
  18. 18.
    Gardella S, Andrei C, Poggi A, et al. Control of interleukin-18 secretion by dendritic cells: role of calcium influxes. FEBS Lett. 2000;481:245–8.CrossRefGoogle Scholar
  19. 19.
    Kakkar R, Hei H, Dobner S, et al. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem. 2012;287:6941–8.CrossRefGoogle Scholar
  20. 20.
    Gardella S, Andrei C, Ferrera D, et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 2002;3:995–1001.CrossRefGoogle Scholar
  21. 21.
    Manthiram K, Zhou Q, Aksentijevich I, et al. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18:832–42.CrossRefGoogle Scholar
  22. 22.
    Agostini L, Martinon F, Burns K, et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20:319–25.CrossRefGoogle Scholar
  23. 23.
    Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11:633–52.CrossRefGoogle Scholar
  24. 24.
    Carta S, Semino C, Sitia R, et al. Dysregulated IL-1β secretion in autoinflammatory diseases: a matter of stress? Front Immunol. 2017;8:345.CrossRefGoogle Scholar
  25. 25.
    Carta S, Penco F, Lavieri R, et al. Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance. Proc Natl Acad Sci U S A. 2015;112:2835–40.CrossRefGoogle Scholar
  26. 26.
    Rodriguez-Smith J, Lin YC, Tsai WL, et al. Cerebrospinal fluid cytokines correlate with aseptic meningitis and blood-brain barrier function in neonatal-onset multisystem inflammatory disease: central nervous system biomarkers in neonatal-onset multisystem inflammatory disease correlate with central nervous system inflammation. Arthritis Rheumatol. 2017;69:1325–36.CrossRefGoogle Scholar
  27. 27.
    Lukens JR, Vogel P, Johnson GR, et al. RIP1-driven autoinflammation targets IL-1 independently of inflammasomes and RIP3. Nature. 2013;498:224–7.CrossRefGoogle Scholar
  28. 28.
    Mazodier K, Marin V, Novick D, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005;106:3483–9.CrossRefGoogle Scholar
  29. 29.
    Canna SW, Girard C, Malle L, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139:1698–701.CrossRefGoogle Scholar
  30. 30.
    Novick D, Kim SH, Fantuzzi G, et al. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 1999;10:127–36.CrossRefGoogle Scholar
  31. 31.
    Kim ML, Chae JJ, Park YH, et al. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β. J Exp Med. 2015;212:927–38.CrossRefGoogle Scholar
  32. 32.
    Bonekamp N, Caorsi R, Viglizzo GM, et al. High-dose ustekinumab for severe childhood deficiency of interleukin-36 receptor antagonist (DITRA). Ann Rheum Dis. 2018;77(8):1241–3.PubMedGoogle Scholar
  33. 33.
    Tassi S, Carta S, Delfino L, et al. Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1beta secretion. Proc Natl Acad Sci U S A. 2010;107:9789–94.CrossRefGoogle Scholar
  34. 34.
    Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208:519–33.CrossRefGoogle Scholar
  35. 35.
    Skendros P, Chrysanthopoulou A, Rousset F, et al. Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1β-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps. J Allergy Clin Immunol. 2017;140:1378–87.CrossRefGoogle Scholar
  36. 36.
    Hall JC, Rosen A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat Rev Rheumatol. 2010;6:40–9.CrossRefGoogle Scholar
  37. 37.
    Ishikawa H, Barber GN. The STING pathway and regulation of innate immune signaling in response to DNA pathogens. Cell Mol Life Sci. 2011;68:1157–65.CrossRefGoogle Scholar
  38. 38.
    Fujimoto M, Tsutsui H, Xinshou O, et al. Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases. Int Immunol. 2004;16:303–14.CrossRefGoogle Scholar
  39. 39.
    Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36–49.CrossRefGoogle Scholar
  40. 40.
    Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91–8.CrossRefGoogle Scholar
  41. 41.
    Rice GI, Kasher PR, Forte GM, et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012;44:1243–8.CrossRefGoogle Scholar
  42. 42.
    Hofer MJ, Campbell IL. Type I interferon in neurological disease-the devil from within. Cytokine Growth Factor Rev. 2013;24:257–67.CrossRefGoogle Scholar
  43. 43.
    Brehm A, Liu Y, Sheikh A, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125:4196–211.CrossRefGoogle Scholar
  44. 44.
    Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18.CrossRefGoogle Scholar
  45. 45.
    Jeremiah N, Neven B, Gentili M, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124:5516–20.CrossRefGoogle Scholar
  46. 46.
    Picard C, Thouvenin G, Kannengiesser C, et al. Severe pulmonary fibrosis as the first manifestation of interferonopathy (TMEM173 mutation). Chest. 2016;150:e65–71.CrossRefGoogle Scholar
  47. 47.
    Frémond ML, Rodero MP, Jeremiah N, et al. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016;138:1752–5.CrossRefGoogle Scholar
  48. 48.
    Seo J, Kang JA, Suh DI, et al. Tofacitinib relieves symptoms of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173. J Allergy Clin Immunol. 2017;139:1396–9.CrossRefGoogle Scholar
  49. 49.
    König N, Fiehn C, Wolf C, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2017;76:468–72.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PediatricsUniversity Hospital Carl Gustav CarusDresdenGermany
  2. 2.Cell Biology UnitIRCCS Ospedale Policlinico San MartinoGenoaItaly

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