Epigenetics in Autoinflammation

  • Clara Lorente-Sorolla
  • Mihai G. Netea
  • Esteban BallestarEmail author


The molecular mechanisms of inflammation involve a series of processes that start as extracellular signals that interact with membrane-bound receptors, cell signaling cascades, nuclear factors, and epigenetic enzymes that activate a specific gene expression program. Environmental factors and/or genetic defects can result in constitutive activation of this program. Recent studies highlight the relevance of epigenetic (dys)regulation in these processes and suggest several implications of these mechanisms and alterations in the clinical management of patients with autoinflammatory diseases. In this chapter, we provide an overview of the latest findings related to the epigenetic control in the function of myeloid cells as main effectors of inflammation, as well as the latest findings in the field of autoinflammatory diseases.


Autoinflammation Epigenetics DNA methylation Myeloid cells 







Activation-induced cytidine deaminase


Absent in melanoma 2


Activator protein


Apoptosis-associated speck-like protein


CCAAT/enhancer binding protein


Cryopyrin-associated periodic syndromes


Crohn disease


Chronic non-bacterial osteomyelitis


cAMP response element-binding protein


Danger-associated molecular patterns


DNA methyltransferases


Early B cell factor 1


E26 transformation-specific


Familial cold autoinflammatory syndrome


Familial Mediterranean fever


Histone acetyltransferases


Histone deacetylases


Hyperimmunoglobulinemia D syndrome


Histone methyltransferases


Hematopoietic stem cells


IκB kinases




Interleukin-1 receptor-associated kinases


Interferon-regulatory factors


Intronic enhancer element


Jumonji domain-containing proteins


c-Jun N-terminal kinases




Mitogen-activated protein kinases


Mevalonate kinase deficiency


Muckle-Wells syndrome


NOD-like receptor


Neonatal-onset multisystem inflammatory disease


Pathogen-associated molecular patterns


Paired box protein 5


Prostaglandin E2


Pattern-recognition receptors


Signal transducer and activator of transcription


Ten-eleven translocation


Tumor necrosis factor


Tumor necrosis factor receptor-associated factor


  1. 1.
    Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35.CrossRefGoogle Scholar
  2. 2.
    Netea MG, Balkwill F, Chonchol M, et al. A guiding map for inflammation. Nat Immunol. 2017;18:826–31.CrossRefGoogle Scholar
  3. 3.
    Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010;140:771–6.CrossRefGoogle Scholar
  4. 4.
    Foster SL, Medzhitov R. Gene-specific control of the TLR-induced inflammatory response. Clin Immunol. 2009;130:7–15.CrossRefGoogle Scholar
  5. 5.
    Guo H, Callaway JB, Ting JP-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.CrossRefGoogle Scholar
  6. 6.
    Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol. 2015;10:395–424.CrossRefGoogle Scholar
  7. 7.
    Álvarez-Errico D, Vento-Tormo R, Ballestar E. Genetic and epigenetic determinants in autoinflammatory diseases. Front Immunol. 2017;8:318.Google Scholar
  8. 8.
    Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror Autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.CrossRefGoogle Scholar
  9. 9.
    Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141–9.CrossRefGoogle Scholar
  10. 10.
    Bird A. Perceptions of epigenetics. Nature. 2007;447:396–8.CrossRefGoogle Scholar
  11. 11.
    Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81.CrossRefGoogle Scholar
  12. 12.
    Ko M, An J, Rao A. DNA methylation and hydroxymethylation in hematologic differentiation and transformation. Curr Opin Cell Biol. 2015;37:91–101.CrossRefGoogle Scholar
  13. 13.
    Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502:472–9.CrossRefGoogle Scholar
  14. 14.
    Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705.CrossRefGoogle Scholar
  15. 15.
    Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell. 2007;128:707–19.CrossRefGoogle Scholar
  16. 16.
    Álvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. 2015;15:7–17.CrossRefGoogle Scholar
  17. 17.
    Ji H, Ehrlich LIR, Seita J, et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature. 2010;467:338–42.CrossRefGoogle Scholar
  18. 18.
    Sun D, Luo M, Jeong M, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14:673–88.CrossRefGoogle Scholar
  19. 19.
    Kallin EM, Rodríguez-Ubreva J, Christensen J, et al. Tet2 facilitates the derepression of myeloid target genes during CEBPα-Induced transdifferentiation of Pre-B cells. Mol Cell. 2012;48:266–76.CrossRefGoogle Scholar
  20. 20.
    Dominguez PM, Teater M, Chambwe N, et al. DNA methylation dynamics of germinal center B cells are mediated by AID. Cell Rep. 2015;12:2086–98.CrossRefGoogle Scholar
  21. 21.
    Andricovich J, Kai Y, Peng W, Foudi A, Tzatsos A. Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis. J Clin Invest. 2016;126:905–20.CrossRefGoogle Scholar
  22. 22.
    Azagra A, Román-González L, Collazo O, et al. In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development. J Exp Med. 2016.Google Scholar
  23. 23.
    Smale ST, Tarakhovsky A, Natoli G. Chromatin contributions to the regulation of innate immunity. Annu Rev Immunol. 2014;32:489–511.CrossRefGoogle Scholar
  24. 24.
    Stender JD, Glass CK. Epigenomic control of the innate immune response. Curr Opin Pharmacol. 2013;13:582–7.CrossRefGoogle Scholar
  25. 25.
    Vento-Tormo R, Company C, Rodríguez-Ubreva J, et al. IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biol. 2016;17:4.Google Scholar
  26. 26.
    Yang X, Wang X, Liu D, Yu L, Xue B, Shi H. Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol Endocrinol. 2014;28:565–74.CrossRefGoogle Scholar
  27. 27.
    Saeed S, Quintin J, Kerstens HHD, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204):1251086.CrossRefGoogle Scholar
  28. 28.
    Stoffels M, Kastner DL. Old dogs, new tricks: monogenic autoinflammatory disease unleashed. Annu Rev Genomics Hum Genet. 2016;17:245–72.CrossRefGoogle Scholar
  29. 29.
    Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18:832–42.CrossRefGoogle Scholar
  30. 30.
    Vento-Tormo R, Álvarez-Errico D, Garcia-Gomez A, et al. DNA demethylation of inflammasome-associated genes is enhanced in patients with cryopyrin-associated periodic syndromes. J Allergy Clin Immunol. 2017;139:202–211.e6.CrossRefGoogle Scholar
  31. 31.
    Aubert P, Suárez-Fariñas M, Mitsui H, et al. Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1β. PLoS One. 2012;7(11):e49408.CrossRefGoogle Scholar
  32. 32.
    Kirectepe AK, Kasapcopur O, Arisoy N, et al. Analysis of MEFV exon methylation and expression patterns in familial Mediterranean fever. BMC Med Genet. 2011;12:105.Google Scholar
  33. 33.
    Latsoudis H, Mashreghi MF, Grün JR, et al. Differential expression of miR-4520a associated with pyrin mutations in Familial Mediterranean Fever (FMF). J Cell Physiol. 2017;232:1326–36.CrossRefGoogle Scholar
  34. 34.
    Bekkering S, Arts RJW, Novakovic B, et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell. 2018;172:135–146.e9.CrossRefGoogle Scholar
  35. 35.
    Hughes T, Ture-Ozdemir F, Alibaz-Oner F, Coit P, Direskeneli H, Sawalha AH. Epigenome-wide scan identifies a treatment-responsive pattern of altered dna methylation among cytoskeletal remodeling genes in monocytes and cd4+ t cells from patients with behçet’s disease. Arthritis Rheumatol. 2014;66:1648–58.CrossRefGoogle Scholar
  36. 36.
    Hofmann SR, Kubasch AS, Ioannidis C, et al. Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1β expression and release. Clin Immunol. 2015;161:300–7.CrossRefGoogle Scholar
  37. 37.
    Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–25.CrossRefGoogle Scholar
  38. 38.
    Nimmo ER, Prendergast JG, Aldhous MC, et al. Genome-wide methylation profiling in Crohn’s disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway. Inflamm Bowel Dis. 2012;18:889–99.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Clara Lorente-Sorolla
    • 1
  • Mihai G. Netea
    • 2
    • 3
  • Esteban Ballestar
    • 1
    Email author
  1. 1.Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC)Bellvitge Biomedical Research Institute (IDIBELL)BarcelonaSpain
  2. 2.Department of Internal Medicine, Radboudumc Expertisecenter on Immunodeficiency and AutoinflammationRadboud University Medical CenterNijmegenThe Netherlands
  3. 3.Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES)University of BonnBonnGermany

Personalised recommendations