Interleukin-33 in health and disease

Key Points

  • Broad expression in stromal and barrier tissue renders interleukin-33 (IL-33) a ubiquitous and crucial immune modulator that shapes type 1, type 2 and regulatory immune responses.

  • Although lacking a secretion sequence and sequestered in the nucleus, IL-33 is released and processed into highly active forms by various proteases.

  • IL-33 contributes to cytokine networks that not only control pathogen removal but also support tissue repair mediated by group 2 innate lymphoid cells and regulatory T cells.

  • The role of IL-33 is expected to continue to expand, modulating both protective and pathological immune responses.

  • Delivering or blocking IL-33 is emerging as a promising therapeutic strategy for maintaining immune homeostasis and protecting against infectious and inflammatory diseases.

Abstract

Interleukin-33 (IL-33) — a member of the IL-1 family — was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8+ T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The interleukin-33 gene and protein structure.
Figure 2: Regulation of IL-33 activity.
Figure 3: IL-33 signalling.
Figure 4: Effects of IL-33 activity in the lungs and gut.

Accession codes

Accessions

Protein Data Bank

References

  1. 1

    Schmitz, J. et al. 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 (2005). This study identifies IL-33 as a cytokine from the IL-1 family and a ligand for ST2, an orphan receptor of the IL-1R family.

  2. 2

    Xu, D. et al. Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J. Exp. Med. 187, 787–794 (1998). This work shows that ST2 is selectively and stably expressed by T H 2 cells and mediates T H 2 cell functions.

  3. 3

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

  4. 4

    Baekkevold, E. S. et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am. J. Pathol. 163, 69–79 (2003).

  5. 5

    Moffatt, M. F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

  6. 6

    Torgerson, D. G. et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat. Genet. 43, 887–892 (2011).

  7. 7

    Talabot-Ayer, D. et al. The mouse interleukin (Il)33 gene is expressed in a cell type- and stimulus-dependent manner from two alternative promoters. J. Leukoc. Biol. 91, 119–125 (2012).

  8. 8

    Lingel, A. et al. Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors—insight into heterotrimeric IL-1 signaling complexes. Structure 17, 1398–1410 (2009). References 8 and 9 reveal the three-dimensional structure of IL-33 and the molecular mechanisms of high-affinity binding to ST2.

  9. 9

    Liu, X. et al. Structural insights into the interaction of IL-33 with its receptors. Proc. Natl Acad. Sci. USA 110, 14918–14923 (2013).

  10. 10

    Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007). This paper demonstrates that IL-33 is a nuclear cytokine in vivo.

  11. 11

    Roussel, L., Erard, M., Cayrol, C. & Girard, J. P. Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket. EMBO Rep. 9, 1006–1012 (2008).

  12. 12

    Ali, S. et al. The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription. J. Immunol. 187, 1609–1616 (2011).

  13. 13

    Bessa, J. et al. Altered subcellular localization of IL-33 leads to non-resolving lethal inflammation. J. Autoimmun. 55, 33–41 (2014). This study shows that genetic deletion of the N-terminal chromatin-binding nuclear domain of IL-33 results in multi-organ inflammation and ST2-dependent lethality.

  14. 14

    Kearley, J. et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity 42, 566–579 (2015). This reference reveals the crucial role of IL-33 in type 1 inflammatory responses in the lungs following viral infection and exposure to cigarette smoke.

  15. 15

    Bonilla, W. V. et al. The alarmin interleukin-33 drives protective antiviral CD8 T cell responses. Science 335, 984–989 (2012).

  16. 16

    Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009).

  17. 17

    Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J. & Kipnis, J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703–709 (2015).

  18. 18

    Lefrancais, E. et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc. Natl Acad. Sci. USA 109, 1673–1678 (2012). This study and reference 49 show that inflammatory proteases process full length IL-33 into shorter forms that have greatly increased biological activity.

  19. 19

    Moussion, C., Ortega, N. & Girard, J. P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS ONE 3, e3331 (2008).

  20. 20

    Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009). References 16 and 20 show that full length IL-33 is biologically active and functions as an alarmin, is released after cellular necrosis, and is inactivated by caspases during apoptosis.

  21. 21

    Talabot-Ayer, D., Lamacchia, C., Gabay, C. & Palmer, G. Interleukin-33 is biologically active independently of caspase-1 cleavage. J. Biol. Chem. 284, 19420–19426 (2009).

  22. 22

    Kouzaki, H., Iijima, K., Kobayashi, T., O'Grady, S. M. & Kita, H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. J. Immunol. 186, 4375–4387 (2011).

  23. 23

    Kamijo, S. et al. IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation. J. Immunol. 190, 4489–4499 (2013).

  24. 24

    Cohen, E. S. et al. Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation. Nat. Commun. 6, 8327 (2015).

  25. 25

    Haenuki, Y. et al. A critical role of IL-33 in experimental allergic rhinitis. J. Allergy Clin. Immunol. 130, 184–194 e111 (2012).

  26. 26

    Byers, D. E. et al. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J. Clin. Invest. 123, 3967–3982 (2013).

  27. 27

    Hudson, C. A. et al. Induction of IL-33 expression and activity in central nervous system glia. J. Leukoc. Biol. 84, 631–643 (2008).

  28. 28

    Chen, W. Y., Hong, J., Gannon, J., Kakkar, R. & Lee, R. T. Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33. Proc. Natl Acad. Sci. USA 112, 7249–7254 (2015).

  29. 29

    Kakkar, R., Hei, H., Dobner, S. & Lee, R. T. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J. Biol. Chem. 287, 6941–6948 (2012).

  30. 30

    Rickard, J. A. et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).

  31. 31

    Pichery, M. et al. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J. Immunol. 188, 3488–3495 (2012).

  32. 32

    Kuchler, A. M. et al. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am. J. Pathol. 173, 1229–1242 (2008).

  33. 33

    Xi, H. et al. IL-33 amplifies an innate immune response in the degenerating retina. J. Exp. Med. 213, 189–207 (2016).

  34. 34

    Molofsky, A. B. et al. Interleukin-33 and interferon-γ counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity 43, 161–174 (2015).

  35. 35

    Carlock, C. I. et al. Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis. J. Immunol. 193, 161–169 (2014).

  36. 36

    Sedhom, M. A. et al. Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut 62, 1714–1723 (2013).

  37. 37

    Prefontaine, D. et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J. Immunol. 183, 5094–5103 (2009).

  38. 38

    Hardman, C. S., Panova, V. & McKenzie, A. N. IL-33 citrine reporter mice reveal the temporal and spatial expression of IL-33 during allergic lung inflammation. Eur. J. Immunol. 43, 488–498 (2013).

  39. 39

    Reichenbach, D. K. et al. The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. Blood 125, 3183–3192 (2015).

  40. 40

    Savinko, T. et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J. Invest. Dermatol. 132, 1392–1400 (2012).

  41. 41

    Yasuda, K. et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc. Natl Acad. Sci. USA 109, 3451–3456 (2012).

  42. 42

    Barlow, J. L. et al. IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J. Allergy Clin. Immunol. 132, 933–941 (2013).

  43. 43

    Marvie, P. et al. Interleukin-33 overexpression is associated with liver fibrosis in mice and humans. J. Cell. Mol. Med. 14, 1726–1739 (2009).

  44. 44

    Masamune, A. et al. Nuclear expression of interleukin-33 in pancreatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G821–832 (2010).

  45. 45

    Manetti, M. et al. The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. Ann. Rheum. Dis. 69, 598–605 (2010).

  46. 46

    Sponheim, J. et al. Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts. Am. J. Path 177, 2804–2815 (2010).

  47. 47

    Nakanishi, W. et al. IL-33, but not IL-25, is crucial for the development of house dust mite antigen-induced allergic rhinitis. PLoS ONE 8, e78099 (2013).

  48. 48

    Mager, L. F. et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J. Clin. Invest. 125, 2579–2591 (2015).

  49. 49

    Lefrancais, E. et al. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc. Natl Acad. Sci. USA 111, 15502–15507 (2014).

  50. 50

    Mohapatra, A. et al. Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol. 9, 275–286 (2015).

  51. 51

    Kim, L. K. et al. AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites. Proc. Natl Acad. Sci. USA 112, E2891–E2899 (2015).

  52. 52

    Madouri, F. et al. Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation. J. Mol. Cell. Biol. 7, 351–365 (2015).

  53. 53

    Sanada, S. et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J. Clin. Invest. 117, 1538–1549 (2007). This work demonstrates that IL-33 has a cardio-protective role.

  54. 54

    Bae, S. et al. Contradictory functions (activation/termination) of neutrophil proteinase 3 enzyme (PR3) in interleukin-33 biological activity. J. Biol. Chem. 287, 8205–8213 (2012).

  55. 55

    Tominaga, S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 258, 301–304 (1989).

  56. 56

    Yanagisawa, K., Takagi, T., Tsukamoto, T., Tetsuka, T. & Tominaga, S. Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin 1 receptor type 1. FEBS Lett. 318, 83–87 (1993).

  57. 57

    Bergers, G., Reikerstorfer, A., Braselmann, S., Graninger, P. & Busslinger, M. Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J. 13, 1176–1188 (1994).

  58. 58

    Lott, J. M., Sumpter, T. L. & Turnquist, H. R. New dog and new tricks: evolving roles for IL-33 in type 2 immunity. J. Leukoc. Biol. 97, 1037–1048 (2015).

  59. 59

    Molofsky, A. B., Savage, A. K. & Locksley, R. M. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42, 1005–1019 (2015).

  60. 60

    Lohning, M. et al. T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc. Natl Acad. Sci. USA 95, 6930–6935 (1998).

  61. 61

    Guo, L. et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc. Natl Acad. Sci. USA 106, 13463–13468 (2009).

  62. 62

    Turnquist, H. R. et al. IL-33 expands suppressive CD11b+ Gr-1(int) and regulatory T cells, including ST2L+ Foxp3+ cells, and mediates regulatory T cell-dependent promotion of cardiac allograft survival. J. Immunol. 187, 4598–4610 (2011). This paper demonstrates that IL-33 induces the expansion of T reg cell populations.

  63. 63

    Matta, B. M. et al. IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells. J. Immunol. 193, 4010–4020 (2014).

  64. 64

    Matta, B. M. et al. Peri-alloHCT IL-33 administration expands recipient T regulatory cells that protect mice against acute GVHD. Blood 128, 427–439 (2016).

  65. 65

    Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015).

  66. 66

    Kolodin, D. et al. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell. Metab. 21, 543–557 (2015).

  67. 67

    Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015). This work established that T cell receptor-independent, IL-33-driven upregulation of AREG supports lung epithelial integrity during viral infections.

  68. 68

    Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014). This study reveals a T reg cell-supportive role for endogenous IL-33 and provides molecular evidence that IL-23 can inhibit IL-33-mediated signalling in T reg cells.

  69. 69

    Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).

  70. 70

    Zaiss, D. M., Gause, W. C., Osborne, L. C. & Artis, D. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42, 216–226 (2015).

  71. 71

    Moro, K. et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 463, 540–544 (2010).

  72. 72

    Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

  73. 73

    Price, A. E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl Acad. Sci. USA 107, 11489–11494 (2010). References 71–73 identify ILC2s as major targets of IL-33 in vivo.

  74. 74

    Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).

  75. 75

    Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).

  76. 76

    Mjosberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).

  77. 77

    Yagi, R. et al. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40, 378–388 (2014).

  78. 78

    Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

  79. 79

    Eberl, G., Di Santo, J. P. & Vivier, E. The brave new world of innate lymphoid cells. Nat. Immunol. 16, 1–5 (2015).

  80. 80

    Huang, Y. & Paul, W. E. Inflammatory group 2 innate lymphoid cells. Int. Immunol. 28, 23–28 (2016).

  81. 81

    Turnquist, H. R. et al. IL-1β-driven ST2L expression promotes maturation resistance in rapamycin-conditioned dendritic cells. J. Immunol. 181, 62–72 (2008).

  82. 82

    Rank, M. A. et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J. Allergy Clin. Immunol. 123, 1047–1054 (2009).

  83. 83

    Turnquist, H. R. et al. mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPS. Blood 115, 4758–4769 (2010).

  84. 84

    Oshikawa, K., Yanagisawa, K., Tominaga, S. & Sugiyama, Y. Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin. Exp. Allergy 32, 1520–1526 (2002).

  85. 85

    Besnard, A. G. et al. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur. J. Immunol. 41, 1675–1686 (2011).

  86. 86

    Morita, H. et al. An interleukin-33-mast cell-interleukin-2 axis suppresses papain-induced allergic inflammation by promoting regulatory T cell numbers. Immunity 43, 175–186 (2015). This report, and reference 63, show that IL-33 supports T reg cell expansion by inducing innate cell production of IL-2.

  87. 87

    Yang, Q. et al. IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8+ T cells. Eur. J. Immunol. 41, 3351–3360 (2011).

  88. 88

    Gao, X. et al. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J. Immunol. 194, 438–445 (2015).

  89. 89

    Baumann, C. et al. T-Bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proc. Natl Acad. Sci. USA 112, 4056–4061 (2015). This study and reference 15 use IL-33- and ST2-deficient mice to demonstrate the role of IL-33 in type 1 immune responses during viral infections.

  90. 90

    Smithgall, M. D. et al. IL-33 amplifies both Th1 and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int. Immunol. 20, 1019–1030 (2008).

  91. 91

    Bourgeois, E. et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-γ production. Eur. J. Immunol. 39, 1046–1055 (2009).

  92. 92

    Kumar, S., Tzimas, M. N., Griswold, D. E. & Young, P. R. Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem. Biophys. Res. Commun. 235, 474–478 (1997).

  93. 93

    Mildner, M. et al. Primary sources and immunological prerequisites for sST2 secretion in humans. Cardiovasc. Res. 87, 769–777 (2010).

  94. 94

    Bulek, K. et al. The essential role of single Ig IL-1 receptor-related molecule/Toll IL-1R8 in regulation of Th2 immune response. J. Immunol. 182, 2601–2609 (2009).

  95. 95

    Zhao, J. et al. F-Box protein FBXL19-mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation. Nat. Immunol. 13, 651–658 (2012).

  96. 96

    Buck, A. H. et al. Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat. Commun. 5, 5488 (2014).

  97. 97

    Humphreys, N. E., Xu, D., Hepworth, M. R., Liew, F. Y. & Grencis, R. K. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 180, 2443–2449 (2008). This study shows that IL-33 is important in protecting the host against infections.

  98. 98

    Hung, L. Y. et al. IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms. Proc. Natl Acad. Sci. USA 110, 282–287 (2013).

  99. 99

    Wilson, S. et al. A late IL-33 response after exposure to Schistosoma haematobium antigen is associated with an up-regulation of IL-13 in human eosinophils. Parasite Immunol. 35, 224–228 (2013).

  100. 100

    Hepworth, M. R., Maurer, M. & Hartmann, S. Regulation of type 2 immunity to helminths by mast cells. Gut Microbes 3, 476–481 (2012).

  101. 101

    Halim, T. Y., Krauss, R. H., Sun, A. C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).

  102. 102

    Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).

  103. 103

    Turner, J. E. et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013).

  104. 104

    Van Dyken, S. J. et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40, 414–424 (2014).

  105. 105

    Salimi, M. et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210, 2939–2950 (2013).

  106. 106

    Vannella, K. M. et al. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci. Transl. Med. 8, 337ra365 (2016).

  107. 107

    Howard, J. G., Hale, C. & Liew, F. Y. Immunological regulation of experimental cutaneous leishmaniasis. III. Nature and significance of specific suppression of cell-mediated immunity in mice highly susceptible to Leishmania tropica. J. Exp. Med. 152, 594–607 (1980).

  108. 108

    Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

  109. 109

    Kropf, P., Bickle, Q., Herath, S., Klemenz, R. & Muller, I. Organ-specific distribution of CD4+ T1/ST2+ Th2 cells in Leishmania major infection. Eur. J. Immunol. 32, 2450–2459 (2002).

  110. 110

    Rostan, O. et al. The IL-33/ST2 axis is associated with human visceral leishmaniasis and suppresses Th1 responses in the livers of BALB/c mice infected with Leishmania donovani. MBio 4, e00383–00313 (2013).

  111. 111

    Gazzinelli, R. T. et al. Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153, 2533–2543 (1994).

  112. 112

    Coombes, J. L. & Hunter, C. A. Immunity to Toxoplasma gondii—into the 21st century. Parasite Immunol. 37, 105–107 (2015).

  113. 113

    Jones, L. A. et al. IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii. Eur. J. Immunol. 40, 426–436 (2010).

  114. 114

    Ayimba, E. et al. Proinflammatory and regulatory cytokines and chemokines in infants with uncomplicated and severe Plasmodium falciparum malaria. Clin. Exp. Immunol. 166, 218–226 (2011).

  115. 115

    Besnard, A. G. et al. IL-33-mediated protection against experimental cerebral malaria is linked to induction of type 2 innate lymphoid cells, M2 macrophages and regulatory T cells. PLoS Pathog. 11, e1004607 (2015).

  116. 116

    Le, H. T. et al. IL-33 priming regulates multiple steps of the neutrophil-mediated anti-Candida albicans response by modulating TLR and dectin-1 signals. J. Immunol. 189, 287–295 (2012).

  117. 117

    Nelson, M. P. et al. IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina. J. Immunol. 186, 2372–2381 (2011).

  118. 118

    Piehler, D. et al. T1/ST2 promotes T helper 2 cell activation and polyfunctionality in bronchopulmonary mycosis. Mucosal Immunol. 6, 405–414 (2013).

  119. 119

    Flaczyk, A. et al. IL-33 signaling regulates innate and adaptive immunity to Cryptococcus neoformans. J. Immunol. 191, 2503–2513 (2013).

  120. 120

    Brunner, M. et al. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med. 30, 1468–1473 (2004).

  121. 121

    Hoogerwerf, J. J. et al. Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med. 36, 630–637 (2010).

  122. 122

    Alves-Filho, J. C. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat. Med. 16, 708–712 (2010).

  123. 123

    Li, C. et al. Interleukin-33 increases antibacterial defense by activation of inducible nitric oxide synthase in skin. PLoS Pathog. 10, e1003918 (2014).

  124. 124

    Malcolm, J. et al. IL-33 exacerbates periodontal disease through induction of RANKL. J. Dent. Res. 94, 968–975 (2015).

  125. 125

    Hazlett, L. D. et al. IL-33 shifts macrophage polarization, promoting resistance against Pseudomonas aeruginosa keratitis. Invest. Ophthalmol. Vis. Sci. 51, 1524–1532 (2010).

  126. 126

    Yin, H. et al. IL-33 promotes Staphylococcus aureus-infected wound healing in mice. Int. Immunopharmacol. 17, 432–438 (2013).

  127. 127

    Boomer, J. S. et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306, 2594–2605 (2011).

  128. 128

    Otto, G. P. et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit. Care 15, R183 (2011).

  129. 129

    Hoogerwerf, J. J. et al. Loss of suppression of tumorigenicity 2 (ST2) gene reverses sepsis-induced inhibition of lung host defense in mice. Am. J. Respir. Crit. Care Med. 183, 932–940 (2011).

  130. 130

    Becerra, A., Warke, R. V., de Bosch, N., Rothman, A. L. & Bosch, I. Elevated levels of soluble ST2 protein in dengue virus infected patients. Cytokine 41, 114–120 (2008).

  131. 131

    Miyagaki, T. et al. High levels of soluble ST2 and low levels of IL-33 in sera of patients with HIV infection. J. Invest. Dermatol. 131, 794–796 (2011).

  132. 132

    Walzl, G. et al. Inhibition of T1/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Th1-driven immunopathology. J. Exp. Med. 193, 785–792 (2001).

  133. 133

    Aoki, R. et al. Mast cells play a key role in host defense against herpes simplex virus infection through TNF-alpha and IL-6 production. J. Invest. Dermatol. 133, 2170–2179 (2013).

  134. 134

    Sesti-Costa, R. et al. The IL-33/ST2 pathway controls coxsackievirus B5-induced experimental pancreatitis. J. Immunol. 191, 283–292 (2013).

  135. 135

    Chang, Y. J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).

  136. 136

    Kayamuro, H. et al. Interleukin-1 family cytokines as mucosal vaccine adjuvants for induction of protective immunity against influenza virus. J. Virol. 84, 12703–12712 (2010).

  137. 137

    Kurowska-Stolarska, M. et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J. Immunol. 183, 6469–6477 (2009). This paper shows that IL-33 can polarize macrophages to the M2 phenotype.

  138. 138

    Sakashita, M. et al. Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis. Clin. Exp. Allergy 38, 1875–1881 (2008).

  139. 139

    Bartemes, K. R. et al. IL-33-responsive lineage-CD25+CD44hi lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J. Immunol. 188, 1503–1513 (2012).

  140. 140

    Stolarski, B., Kurowska-Stolarska, M., Kewin, P., Xu, D. & Liew, F. Y. IL-33 exacerbates eosinophil-mediated airway inflammation. J. Immunol. 185, 3472–3480 (2010).

  141. 141

    Imai, Y. et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc. Natl Acad. Sci. USA 110, 13921–13926 (2013).

  142. 142

    Shimpo, M. et al. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 109, 2186–2190 (2004). This study reveals the importance of sST2 as a biomarker of clinical cardiovascular disease.

  143. 143

    Miller, A. M. et al. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 205, 339–346 (2008).

  144. 144

    Han, G. W. et al. Serum levels of IL-33 is increased in patients with ankylosing spondylitis. Clin. Rheumatol 30, 1583–1588 (2011).

  145. 145

    Tang, S. et al. Increased IL-33 in synovial fluid and paired serum is associated with disease activity and autoantibodies in rheumatoid arthritis. Clin. Dev. Immunol. 2013, 985301 (2013).

  146. 146

    Li, C. et al. Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis. Arthritis Res. Ther. 16, R105 (2014).

  147. 147

    Leung, B. P., Xu, D., Culshaw, S., McInnes, I. B. & Liew, F. Y. A novel therapy of murine collagen-induced arthritis with soluble T1/ST2. J. Immunol. 173, 145–150 (2004).

  148. 148

    Xu, D. et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Natl Acad. Sci. USA 105, 10913–10918 (2008).

  149. 149

    Palmer, G. et al. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum. 60, 738–749 (2009).

  150. 150

    Komai-Koma, M. et al. IL-33 activates B1 cells and exacerbates contact sensitivity. J. Immunol. 186, 2584–2591 (2011).

  151. 151

    Millar, N. L. et al. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat. Commun. 6, 6774 (2015).

  152. 152

    Kuswanto, W. et al. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity 44, 355–367 (2016). This study uses T reg cell-specific deletion of ST2 to provide definitive evidence for the important role of IL-33 in tissue T reg cell homeostasis and effective muscle repair.

  153. 153

    Pastorelli, L. et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc. Natl Acad. Sci. USA 107, 8017–8022 (2010).

  154. 154

    Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl Acad. Sci. USA 107, 18581–18586 (2010). This work reports the phenotype of Il33−/− mice.

  155. 155

    Duan, L. et al. Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3(+) regulatory T-cell responses in mice. Mol. Med. 18, 753–761 (2012).

  156. 156

    Monticelli, L. A. et al. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc. Natl Acad. Sci. USA 112, 10762–10767 (2015).

  157. 157

    Axelsson, L. G., Landstrom, E., Goldschmidt, T. J., Gronberg, A. & Bylund-Fellenius, A. C. Dextran sulfate sodium (DSS) induced experimental colitis in immunodeficient mice: effects in CD4(+)-cell depleted, athymic and NK-cell depleted SCID mice. Inflamm. Res. 45, 181–191 (1996).

  158. 158

    Miller, A. M. et al. Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ. Res. 107, 650–658 (2010).

  159. 159

    Hasan, A. et al. IL-33 is negatively associated with the BMI and confers a protective lipid/metabolic profile in non-diabetic but not diabetic subjects. BMC Immunol. 15, 19 (2014).

  160. 160

    Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

  161. 161

    Lee, M. W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).

  162. 162

    Barbour, M. et al. IL-33 attenuates the development of experimental autoimmune uveitis. Eur. J. Immunol. 44, 3320–3329 (2014).

  163. 163

    Maywald, R. L. et al. IL-33 activates tumor stroma to promote intestinal polyposis. Proc. Natl Acad. Sci. USA 112, E2487–2496 (2015).

  164. 164

    Levescot, A. et al. BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34+ progenitors from chronic myeloid leukemia patients. Cancer Res. 74, 2669–2676 (2014).

  165. 165

    Brunner, S. M. et al. Interleukin-33 prolongs allograft survival during chronic cardiac rejection. Transpl. Int. 24, 1027–1039 (2011).

  166. 166

    McDonald-Hyman, C., Turka, L. A. & Blazar, B. R. Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation. Sci. Transl. Med. 7, 280rv282 (2015).

  167. 167

    Mathews, L. R. et al. Elevated ST2 distinguishes incidences of pediatric heart and small bowel transplant rejection. Am. J. Transplant. 16, 938–950 (2016).

  168. 168

    Vander Lugt, M. T. et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N. Engl. J. Med. 369, 529–539 (2013).

  169. 169

    Zhang, J. et al. ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Sci. Transl. Med. 7, 308ra160 (2015).

  170. 170

    Ponce, D. M. et al. High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation. Blood 125, 199–205 (2015).

  171. 171

    Pascual-Figal, D. A. et al. Soluble ST2 is a marker for acute cardiac allograft rejection. Ann. Thorac Surg. 92, 2118–2124 (2011).

  172. 172

    Villalta, S. A. et al. Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci. Transl. Med. 6, 258ra142 (2014).

  173. 173

    Rak, G. D. et al. IL-33-dependent group 2 innate lymphoid cells promote cutaneous wound healing. J. Invest. Dermatol. 136, 487–496 (2016).

  174. 174

    Luzina, I. G. et al. Interleukin-33 potentiates bleomycin-induced lung injury. Am. J. Respir. Cell. Mol. Biol. 49, 999–1008 (2013).

  175. 175

    Li, D. et al. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J. Allergy Clin. Immunol. 134, 1422–1432 e1411 (2014).

  176. 176

    McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

  177. 177

    Li, J. et al. Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J. Clin. Invest. 124, 3241–3251 (2014).

  178. 178

    Lee, J. S., Seppanen, E., Patel, J., Rodero, M. P. & Khosrotehrani, K. ST2 receptor invalidation maintains wound inflammation, delays healing and increases fibrosis. Exp. Dermatol. 25, 71–74 (2016).

  179. 179

    Yasuoka, S. et al. Production and functions of IL-33 in the central nervous system. Brain Res. 1385, 8–17 (2011).

  180. 180

    Jiang, H. R. et al. IL-33 attenuates EAE by suppressing IL-17 and IFN-gamma production and inducing alternatively activated macrophages. Eur. J. Immunol. 42, 1804–1814 (2012).

  181. 181

    Luo, Y. et al. Interleukin-33 ameliorates ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response. Brain Res. 1597, 86–94 (2015).

  182. 182

    Pomeshchik, Y. et al. Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury. Brain Behav. Immun. 44, 68–81 (2015).

  183. 183

    Fu, A. K. et al. IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline. Proc. Natl Acad. Sci. USA 113, E2705–2713 (2016).

  184. 184

    Chapuis, J. et al. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Mol. Psychiatry 14, 1004–1016 (2009).

  185. 185

    Yu, J. T. et al. Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease. Neurobiol. Aging 33, 1014 e1011–1014 (2012).

  186. 186

    Brint, E. K. et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat. Immunol. 5, 373–379 (2004).

  187. 187

    Martin, P. et al. Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency. Arthritis Res. Ther. 15, R13 (2013).

Download references

Acknowledgements

F.Y.L is supported by the Wellcome Trust and the Medical Research Council, UK. J.-P.G. is supported by grants from Agence Nationale de la Recherche (ANR-12-BSV3-0005-01), Institut National du Cancer (INCA) and Fondation ARC. H.R.T. is supported by grants from the US National Institutes of Health, National Heart, Lung, and Blood Institutes (R01 HL122489) and the National Institute of Allergy and Infectious Diseases (R21 AI121981).

Author information

Correspondence to Foo Yew Liew.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Principal sources of nuclear IL-33 in human and mouse tissues (PDF 138 kb)

Glossary

IL-1 family

A family of pro-inflammatory cytokines with 11 members, including IL-1β, IL-18 and IL-33. They stimulate the expression of integrins on leukocytes and endothelial cells, regulate and initiate inflammatory responses. They bind to heterodimeric receptors comprised of a specific receptor and a shared IL-1 receptor accessory protein and activate cell signalling through adaptor protein MYD88.

Group 2 innate lymphoid cells

A subset of innate lymphoid cells (ILCs) that produce type 2 cytokines, such as interleukin-5 and interleukin-13. Their development depends on the transcription factors retinoic acid receptor-related orphan receptor-α and GATA-binding protein 3. These cells contribute to tissue repair and parasite elimination, as well as to the development of asthma and allergy.

Alarmin

An endogenous molecule that is released after tissue injury and that promotes activation of the innate immune system. Excessive release of alarmins might promote uncontrolled inflammation and exacerbate tissue injury. Conversely, alarmins may have beneficial effects by activating the immune system to combat potential pathogens. Also called damage-associated molecular pattern (DAMP).

Necroptosis

A programmed form of necrotic cell death mediated by receptor-interacting protein kinase 1 (RIPK1) and RIPK3. It can be induced by death receptors and by TIR-domain-containing adaptor protein inducing interferon-β (TRIF)-dependent Toll-like receptor 3 (TLR3) and TLR4 signalling. Inhibition of caspase 8 activation sensitizes cells to necroptosis.

Chronic obstructive pulmonary disease

(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic obstructive bronchitis and emphysema. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants (such as coal dust) and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Graft versus host disease

(GVHD). Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T lymphocytes that recognize the tissues of the recipient as foreign. GVHD varies markedly in extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.

Myeloproliferative neoplasms

A group of diseases of the bone marrow in which excess cells are produced as a result of clonal genetic changes. It was previously known as myeloproliferative diseases. The increased number of blood cells may not cause any symptoms but may increase the risk of thrombosis.

M2 macrophages

Also known as alternatively-activated macrophages, M2 macrophages differentiate in response to interleukin-4 (IL-4) or IL-13 and are thought to mediate T helper 2-type immune responses, such as protection from parasites and wound healing. They are typically defined by their expression of arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain, and they can produce large amounts of IL-10.

Apolipoprotein E-deficient mice

A widely used mouse model that is prone to develop atherosclerosis because the mice have high levels of types of atherogenic lipoprotein called remnant lipoproteins. This lipoprotein abnormality is cause by the genetic absence of apolipoprotein E (APOE), which normally clears remnant lipoproteins from the bloodstream by interacting with hepatocytes.

B1 cells

An innate-like population of B cells that is mainly found in the peritoneal and pleural cavities of mice. B1 cell precursors develop in the fetal liver and omentum. B1 cells recognize self components as well as common bacterial antigens and secrete antibodies of low affinity and broad specificity.

Tendinopathy

A common disease of the tendon, characterized by tenderness on palpitation and pain, often when exercising or with movement. Tendinopathy is most frequently seen in tendons of athletes either before or after an injury resulting from tensile overload, tendon cell-related collagen synthesis disruption or load-induced ischaemia.

Dextran sodium sulfate (DSS)-induced acute colitis

A commonly used experimental model of colitis induced in mice by ingestion of the sulfated polysaccharide DSS. This model causes acute colonic epithelial damage and inflammation via unknown mechanisms.

T cell transfer-induced colitis

A commonly used mouse model of inflammatory bowel disease based on the disruption of T cell homeostasis. Adoptive transfer of CD4+CD45RBhi T cells (naive T cells) from healthy wild-type mice into syngeneic recipients that lack T cells and B cells induces a pan-colitis and small bowel inflammation at 5–8 weeks following cell transfer, with varying degrees of weight loss and diarrhoea and loose stools. This model allows the examination of the early immunological events associated with the induction of gut inflammation as well as the perpetuation of disease.

White adipose tissue

One of the two types of adipose tissue found in mammals (the other being brown adipose tissue). In healthy, non-overweight humans, It composes 20% in men and 25% in women of body weight. White adipose tissue cells contain a single large fat droplet, which forces the nucleus to be squeezed into the thin rim at the periphery. It is used as a store of energy and also acts as a thermal insulator, helping to maintain body temperature.

Brown adipose tissue

Comprising both cells that share a common embryological origin with muscle cells, and are found in large deposits, and beige cells that develop from white adipocytes, which are stimulated by the sympathetic nervous system and are found interspersed in white adipose tissue. Brown adipocytes contain numerous small fat droplets and a high number of iron-containing mitochondria, which gives them their brown appearance. The primary function is thermoregulation.

ApcMin/+ mouse model

A mouse strain that carries a point mutation in one adenomatous polyposis coli (Apc) allele and spontaneously develops intestinal adenomas. It is used as a model for human familial adenomatous polyposis and for human sporadic colorectal cancer.

Conditioning protocols

(Also known as a preparative regimen). Treatments involving a combination of chemotherapy, radiation therapy and/or immunosuppressive medications that are designed not only to destroy residual malignant cells but also to provide space for donor stem cell engraftment and to provide immunosuppression to prevent host rejection of the donor stem cells.

Microglia

Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are thought to be the major brain-resident macrophages.

APP/PS1 mice

Also known as APPswePS1de9 mice. A commonly used mouse model of Alzheimer disease. These double-transgenic mice are generated by incorporation of a murine or human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both directed to neurons of the central nervous system. These mice develop β-amyloid deposits in the brain, cognitive impairment and have a high incidence of seizures by 6–7 months of age.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liew, F., Girard, J. & Turnquist, H. Interleukin-33 in health and disease. Nat Rev Immunol 16, 676–689 (2016). https://doi.org/10.1038/nri.2016.95

Download citation

Further reading