IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets

  • Hye Young Kim (Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Dongjin Jeong (Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Ji Hyung Kim (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Doo Hyun Chung (Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine)
  • Received : 2023.11.23
  • Accepted : 2024.01.15
  • Published : 2024.02.29
Download PDF
⟨ Previous Next ⟩

Abstract

The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33. Recent advancements in therapeutic strategies, specifically the utilization of biologics targeting pivotal cytokines (IL-4, IL-5, and IL-13), are discussed, offering insights into both challenges and opportunities. Acknowledging the pivotal role of innate type-2 cytokines in orchestrating immune responses positions them as promising therapeutic targets. The evolving landscape of research and development in this field not only propels immunological knowledge forward but also holds the promise of more effective treatments in the future.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (2020R1A2C2008312, RS-2023-00217571, 2021M3A9I2080493, 2022R1A2C3007730, and RS-2023-00217798). All graphics were created with Biorender.com.

References

  1. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197-216. https://doi.org/10.1146/annurev.immunol.20.083001.084359
  2. Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol 2015;15:271-282. https://doi.org/10.1038/nri3831
  3. Licona-Limon P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 2013;14:536-542. https://doi.org/10.1038/ni.2617
  4. Akdis CA, Arkwright PD, Bruggen MC, Busse W, Gadina M, Guttman-Yassky E, Kabashima K, Mitamura Y, Vian L, Wu J, et al. Type 2 immunity in the skin and lungs. Allergy 2020;75:1582-1605. https://doi.org/10.1111/all.14318
  5. Ham J, Shin JW, Ko BC, Kim HY. Targeting the epithelium-derived innate cytokines: from bench to bedside. Immune Netw 2022;22:e11.
  6. McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 family of cytokines in health and disease. Immunity 2019;50:892-906. https://doi.org/10.1016/j.immuni.2019.03.021
  7. Kouzaki H, Tojima I, Kita H, Shimizu T. Transcription of interleukin-25 and extracellular release of the protein is regulated by allergen proteases in airway epithelial cells. Am J Respir Cell Mol Biol 2013;49:741-750. https://doi.org/10.1165/rcmb.2012-0304OC
  8. Min HK, Won JY, Kim BM, Lee KA, Lee SJ, Lee SH, Kim HR, Kim KW. Interleukin (IL)-25 suppresses IL-22-induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway. Arthritis Res Ther 2020;22:222.
  9. Sonobe Y, Takeuchi H, Kataoka K, Li H, Jin S, Mimuro M, Hashizume Y, Sano Y, Kanda T, Mizuno T, et al. Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cepsilon-dependent manner. J Biol Chem 2009;284:31834-31842. https://doi.org/10.1074/jbc.M109.025940
  10. Goswami S, Angkasekwinai P, Shan M, Greenlee KJ, Barranco WT, Polikepahad S, Seryshev A, Song LZ, Redding D, Singh B, et al. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol 2009;10:496-503. https://doi.org/10.1038/ni.1719
  11. Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S, Menon S, Seymour B, Jackson C, Kung TT, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 2002;169:443-453. https://doi.org/10.4049/jimmunol.169.1.443
  12. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001;15:985-995. https://doi.org/10.1016/S1074-7613(01)00243-6
  13. Terashima A, Watarai H, Inoue S, Sekine E, Nakagawa R, Hase K, Iwamura C, Nakajima H, Nakayama T, Taniguchi M. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med 2008;205:2727-2733. https://doi.org/10.1084/jem.20080698
  14. Stock P, Lombardi V, Kohlrautz V, Akbari O. Induction of airway hyperreactivity by IL-25 is dependent on a subset of invariant NKT cells expressing IL-17RB. J Immunol 2009;182:5116-5122. https://doi.org/10.4049/jimmunol.0804213
  15. Owyang AM, Zaph C, Wilson EH, Guild KJ, McClanahan T, Miller HR, Cua DJ, Goldschmidt M, Hunter CA, Kastelein RA, et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med 2006;203:843-849. https://doi.org/10.1084/jem.20051496
  16. Drake LY, Kita H. IL-33: biological properties, functions, and roles in airway disease. Immunol Rev 2017;278:173-184. https://doi.org/10.1111/imr.12552
  17. Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 2008;7:827-840. https://doi.org/10.1038/nrd2660
  18. Cayrol C, Duval A, Schmitt P, Roga S, Camus M, Stella A, Burlet-Schiltz O, Gonzalez-de-Peredo A, Girard JP. Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nat Immunol 2018;19:375-385. https://doi.org/10.1038/s41590-018-0067-5
  19. Lefrancais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP, Cayrol C. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A 2012;109:1673-1678. https://doi.org/10.1073/pnas.1115884109
  20. Roy A, Ganesh G, Sippola H, Bolin S, Sawesi O, Dagalv A, Schlenner SM, Feyerabend T, Rodewald HR, Kjellen L, et al. Mast cell chymase degrades the alarmins heat shock protein 70, biglycan, HMGB1, and interleukin-33 (IL-33) and limits danger-induced inflammation. J Biol Chem 2014;289:237-250. https://doi.org/10.1074/jbc.M112.435156
  21. Cayrol C, Girard JP. Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev 2018;281:154-168. https://doi.org/10.1111/imr.12619
  22. Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 2008;121:1484-1490. https://doi.org/10.1016/j.jaci.2008.04.005
  23. Sehmi R, Smith SG, Kjarsgaard M, Radford K, Boulet LP, Lemiere C, Prazma CM, Ortega H, Martin JG, Nair P. Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy 2016;46:793-802. https://doi.org/10.1111/cea.12695
  24. Tran VG, Cho HR, Kwon B. IL-33 priming enhances peritoneal macrophage activity in response to candida albicans. Immune Netw 2014;14:201-206. https://doi.org/10.4110/in.2014.14.4.201
  25. Kearley J, Buckland KF, Mathie SA, Lloyd CM. Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am J Respir Crit Care Med 2009;179:772-781. https://doi.org/10.1164/rccm.200805-666OC
  26. Yin H, Li XY, Liu T, Yuan BH, Zhang BB, Hu SL, Gu HB, Jin XB, Zhu JY. Adenovirus-mediated delivery of soluble ST2 attenuates ovalbumin-induced allergic asthma in mice. Clin Exp Immunol 2012;170:1-9. https://doi.org/10.1111/j.1365-2249.2012.04629.x
  27. Smith DE. IL-33: a tissue derived cytokine pathway involved in allergic inflammation and asthma. Clin Exp Allergy 2010;40:200-208. https://doi.org/10.1111/j.1365-2222.2009.03384.x
  28. Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol 2019;20:1603-1609. https://doi.org/10.1038/s41590-019-0524-9
  29. Fornasa G, Tsilingiri K, Caprioli F, Botti F, Mapelli M, Meller S, Kislat A, Homey B, Di Sabatino A, Sonzogni A, et al. Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin. J Allergy Clin Immunol 2015;136:413-422. https://doi.org/10.1016/j.jaci.2015.04.011
  30. Pattarini L, Trichot C, Bogiatzi S, Grandclaudon M, Meller S, Keuylian Z, Durand M, Volpe E, Madonna S, Cavani A, et al. TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand. J Exp Med 2017;214:1529-1546. https://doi.org/10.1084/jem.20150402
  31. Ahn S, Jeong D, Oh SJ, Ahn J, Lee SH, Chung DH. GM-CSF and IL-4 produced by NKT cells inversely regulate IL-1β production by macrophages. Immunol Lett 2017;182:50-56. https://doi.org/10.1016/j.imlet.2017.01.003
  32. Brennan PJ, Brigl M, Brenner MB. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 2013;13:101-117. https://doi.org/10.1038/nri3369
  33. Michel ML, Mendes-da-Cruz D, Keller AC, Lochner M, Schneider E, Dy M, Eberl G, Leite-de-Moraes MC. Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc Natl Acad Sci U S A 2008;105:19845-19850. https://doi.org/10.1073/pnas.0806472105
  34. Gumperz JE, Miyake S, Yamamura T, Brenner MB. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med 2002;195:625-636. https://doi.org/10.1084/jem.20011786
  35. Burdin N, Brossay L, Koezuka Y, Smiley ST, Grusby MJ, Gui M, Taniguchi M, Hayakawa K, Kronenberg M. Selective ability of mouse CD1 to present glycolipids: alpha-galactosylceramide specifically stimulates V alpha 14+ NK T lymphocytes. J Immunol 1998;161:3271-3281. https://doi.org/10.4049/jimmunol.161.7.3271
  36. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007;25:297-336. https://doi.org/10.1146/annurev.immunol.25.022106.141711
  37. Georgiev H, Ravens I, Benarafa C, Forster R, Bernhardt G. Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets. Nat Commun 2016;7:13116.
  38. Lee YJ, Starrett GJ, Lee ST, Yang R, Henzler CM, Jameson SC, Hogquist KA. Lineage-specific effector signatures of invariant NKT cells are shared amongst γδ T, innate lymphoid, and Th cells. J Immunol 2016;197:1460-1470. https://doi.org/10.4049/jimmunol.1600643
  39. Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol 2013;14:1146-1154. https://doi.org/10.1038/ni.2731
  40. Baranek T, Lebrigand K, de Amat Herbozo C, Gonzalez L, Bogard G, Dietrich C, Magnone V, Boisseau C, Jouan Y, Trottein F, et al. High dimensional single-cell analysis reveals iNKT cell developmental trajectories and effector fate decision. Cell Reports 2020;32:108116.
  41. Berga-Bolanos R, Sharma A, Steinke FC, Pyaram K, Kim YH, Sultana DA, Fang JX, Chang CH, Xue HH, Heller NM, et al. β-Catenin is required for the differentiation of iNKT2 and iNKT17 cells that augment IL-25-dependent lung inflammation. BMC Immunol 2015;16:62.
  42. Shin SB, McNagny KM. ILC-you in the thymus: a fresh look at innate lymphoid cell development. Front Immunol 2021;12:681110.
  43. Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, et al. Innate lymphoid cells: 10 years on. Cell 2018;174:1054-1066. https://doi.org/10.1016/j.cell.2018.07.017
  44. Zhang J, Marotel M, Fauteux-Daniel S, Mathieu AL, Viel S, Marcais A, Walzer T. T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1. Eur J Immunol 2018;48:738-750. https://doi.org/10.1002/eji.201747299
  45. Chiossone L, Dumas PY, Vienne M, Vivier E. Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol 2018;18:671-688. https://doi.org/10.1038/s41577-018-0061-z
  46. Kortekaas Krohn I, Shikhagaie MM, Golebski K, Bernink JH, Breynaert C, Creyns B, Diamant Z, Fokkens WJ, Gevaert P, Hellings P, et al. Emerging roles of innate lymphoid cells in inflammatory diseases: clinical implications. Allergy 2018;73:837-850. https://doi.org/10.1111/all.13340
  47. Woo Y, Jeong D, Chung DH, Kim HY. The roles of innate lymphoid cells in the development of asthma. Immune Netw 2014;14:171-181. https://doi.org/10.4110/in.2014.14.4.171
  48. Meininger I, Carrasco A, Rao A, Soini T, Kokkinou E, Mjosberg J. Tissue-specific features of innate lymphoid cells. Trends Immunol 2020;41:902-917. https://doi.org/10.1016/j.it.2020.08.009
  49. Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O'Byrne PM, Gauvreau GM, Boulet LP, Lemiere C, Martin J, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol 2016;137:75-86.e8. https://doi.org/10.1016/j.jaci.2015.05.037
  50. Sugita K, Steer CA, Martinez-Gonzalez I, Altunbulakli C, Morita H, Castro-Giner F, Kubo T, Wawrzyniak P, Ruckert B, Sudo K, et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. J Allergy Clin Immunol 2018;141:300-310.e11. https://doi.org/10.1016/j.jaci.2017.02.038
  51. Wallrapp A, Riesenfeld SJ, Burkett PR, Kuchroo VK. Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation. Immunol Rev 2018;286:53-73. https://doi.org/10.1111/imr.12702
  52. Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol 2006;24:147-174. https://doi.org/10.1146/annurev.immunol.24.021605.090720
  53. Karasuyama H, Mukai K, Obata K, Tsujimura Y, Wada T. Nonredundant roles of basophils in immunity. Annu Rev Immunol 2011;29:45-69. https://doi.org/10.1146/annurev-immunol-031210-101257
  54. Voehringer D. Protective and pathological roles of mast cells and basophils. Nat Rev Immunol 2013;13:362-375. https://doi.org/10.1038/nri3427
  55. Xue L, Salimi M, Panse I, Mjosberg JM, McKenzie AN, Spits H, Klenerman P, Ogg G. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol 2014;133:1184-1194. https://doi.org/10.1016/j.jaci.2013.10.056
  56. Karasuyama H, Miyake K, Yoshikawa S, Kawano Y, Yamanishi Y. How do basophils contribute to Th2 cell differentiation and allergic responses? Int Immunol 2018;30:391-396. https://doi.org/10.1093/intimm/dxy026
  57. De Filippo K, Dudeck A, Hasenberg M, Nye E, van Rooijen N, Hartmann K, Gunzer M, Roers A, Hogg N. Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. Blood 2013;121:4930-4937. https://doi.org/10.1182/blood-2013-02-486217
  58. Robinson D, Humbert M, Buhl R, Cruz AA, Inoue H, Korom S, Hanania NA, Nair P. Revisiting type 2-high and type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy 2017;47:161-175. https://doi.org/10.1111/cea.12880
  59. Fukuda T, Fukushima Y, Numao T, Ando N, Arima M, Nakajima H, Sagara H, Adachi T, Motojima S, Makino S. Role of interleukin-4 and vascular cell adhesion molecule-1 in selective eosinophil migration into the airways in allergic asthma. Am J Respir Cell Mol Biol 1996;14:84-94. https://doi.org/10.1165/ajrcmb.14.1.8534490
  60. Doran E, Cai F, Holweg CT, Wong K, Brumm J, Arron JR. Interleukin-13 in asthma and other eosinophilic disorders. Front Med (Lausanne) 2017;4:139.
  61. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science 2012;335:936-941. https://doi.org/10.1126/science.1214935
  62. Artis D, Spits H. The biology of innate lymphoid cells. Nature 2015;517:293-301. https://doi.org/10.1038/nature14189
  63. Acharya KR, Ackerman SJ. Eosinophil granule proteins: form and function. J Biol Chem 2014;289:17406-17415. https://doi.org/10.1074/jbc.R113.546218
  64. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010;464:1367-1370. https://doi.org/10.1038/nature08900
  65. Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, Locksley RM. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 2010;107:11489-11494. https://doi.org/10.1073/pnas.1003988107
  66. Mallevaey T, Zanetta JP, Faveeuw C, Fontaine J, Maes E, Platt F, Capron M, de-Moraes ML, Trottein F. Activation of invariant NKT cells by the helminth parasite schistosoma mansoni. J Immunol 2006;176:2476-2485. https://doi.org/10.4049/jimmunol.176.4.2476
  67. Pawankar R, Canonica GW, Holgate ST, Lockey RF. Allergic diseases and asthma: a major global health concern. Curr Opin Allergy Clin Immunol 2012;12:39-41. https://doi.org/10.1097/ACI.0b013e32834ec13b
  68. Siracusa MC, Kim BS, Spergel JM, Artis D. Basophils and allergic inflammation. J Allergy Clin Immunol 2013;132:789-801. https://doi.org/10.1016/j.jaci.2013.07.046
  69. Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 2010;11:577-584. https://doi.org/10.1038/ni.1892
  70. Aneas I, Decker DC, Howard CL, Sobreira DR, Sakabe NJ, Blaine KM, Stein MM, Hrusch CL, Montefiori LE, Tena J, et al. Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region. Nat Commun 2021;12:6115.
  71. Kim J, Chang Y, Bae B, Sohn KH, Cho SH, Chung DH, Kang HR, Kim HY. Innate immune crosstalk in asthmatic airways: innate lymphoid cells coordinate polarization of lung macrophages. J Allergy Clin Immunol 2019;143:1769-1782.e11. https://doi.org/10.1016/j.jaci.2018.10.040
  72. Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S, Gombert JM, Schneider E, Dy M, Gourdy P, et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol 2009;39:1046-1055. https://doi.org/10.1002/eji.200838575
  73. Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE. 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 2008;20:1019-1030. https://doi.org/10.1093/intimm/dxn060
  74. Gieseck RL 3rd, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 2018;18:62-76. https://doi.org/10.1038/nri.2017.90
  75. Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, De Wever O, Mareel M, Gabbiani G. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 2012;180:1340-1355. https://doi.org/10.1016/j.ajpath.2012.02.004
  76. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med 2011;208:1339-1350. https://doi.org/10.1084/jem.20110551
  77. Fichtner-Feigl S, Strober W, Geissler EK, Schlitt HJ. Cytokines mediating the induction of chronic colitis and colitis-associated fibrosis. Mucosal Immunol 2008;1 Suppl 1:S24-7. https://doi.org/10.1038/mi.2008.41
  78. Yanagi S, Tsubouchi H, Miura A, Matsumoto N, Nakazato M. Breakdown of epithelial barrier integrity and overdrive activation of alveolar epithelial cells in the pathogenesis of acute respiratory distress syndrome and lung fibrosis. BioMed Res Int 2015;2015:573210.
  79. Baurakiades E, Costa VH Jr, Raboni SM, de Almeida VR, Larsen KS, Kohler JN, Gozzo PC, Klassen G, Manica GC, de Noronha L. The roles of ADAM33, ADAM28, IL-13 and IL-4 in the development of lung injuries in children with lethal non-pandemic acute infectious pneumonia. J Clin Virol 2014;61:585-589. https://doi.org/10.1016/j.jcv.2014.10.004
  80. Heitmann L, Abad Dar M, Schreiber T, Erdmann H, Behrends J, Mckenzie AN, Brombacher F, Ehlers S, Holscher C. The IL-13/IL-4Rα axis is involved in tuberculosis-associated pathology. J Pathol 2014;234:338-350. https://doi.org/10.1002/path.4399
  81. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014;14:181-194. https://doi.org/10.1038/nri3623
  82. Li J, Bessho K, Shivakumar P, Mourya R, Mohanty SK, Dos Santos JL, Miura IK, Porta G, Bezerra JA. Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype. J Clin Invest 2011;121:4244-4256. https://doi.org/10.1172/JCI57728
  83. Wang W, Seale P. Control of brown and beige fat development. Nat Rev Mol Cell Biol 2016;17:691-702. https://doi.org/10.1038/nrm.2016.96
  84. Mahlakoiv T, Flamar AL, Johnston LK, Moriyama S, Putzel GG, Bryce PJ, Artis D. Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33. Sci Immunol 2019;4:eaax0416.
  85. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007;447:1116-1120. https://doi.org/10.1038/nature05894
  86. Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 2013;210:535-549. https://doi.org/10.1084/jem.20121964
  87. Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O'Shea D, O'Farrelly C, Exley MA. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 2012;37:574-587. https://doi.org/10.1016/j.immuni.2012.06.016
  88. Hams E, Locksley RM, McKenzie AN, Fallon PG. Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J Immunol 2013;191:5349-5353. https://doi.org/10.4049/jimmunol.1301176
  89. Camelo A, Barlow JL, Drynan LF, Neill DR, Ballantyne SJ, Wong SH, Pannell R, Gao W, Wrigley K, Sprenkle J, et al. Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J Gastroenterol 2012;47:1198-1211. https://doi.org/10.1007/s00535-012-0591-2
  90. O'Byrne PM, Panettieri RA Jr, Taube C, Brindicci C, Fleming M, Altman P. Development of an inhaled anti-TSLP therapy for asthma. Pulm Pharmacol Ther 2023;78:102184.
  91. Karo-Atar D, Bitton A, Benhar I, Munitz A. Therapeutic targeting of the interleukin-4/interleukin-13 signaling pathway: in allergy and beyond. BioDrugs 2018;32:201-220. https://doi.org/10.1007/s40259-018-0280-7
  92. Corren J, Lemanske RF Jr, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088-1098. https://doi.org/10.1056/NEJMoa1106469
  93. Panettieri RA Jr, Sjobring U, Peterffy A, Wessman P, Bowen K, Piper E, Colice G, Brightling CE. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir Med 2018;6:511-525. https://doi.org/10.1016/S2213-2600(18)30184-X
  94. Paul WE, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nat Rev Immunol 2010;10:225-235. https://doi.org/10.1038/nri2735
  95. Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, Olsson RF, Martin UJ, Goldman M, Yanez A, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med 2019;7:46-59. https://doi.org/10.1016/S2213-2600(18)30406-5
  96. Weinstein SF, Katial R, Jayawardena S, Pirozzi G, Staudinger H, Eckert L, Joish VN, Amin N, Maroni J, Rowe P, et al. Efficacy and safety of dupilumab in perennial allergic rhinitis and comorbid asthma. J Allergy Clin Immunol 2018;142:171-177.e1. https://doi.org/10.1016/j.jaci.2017.11.051
  97. Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, Mullol J, Greos LS, Bosso JV, Laidlaw TM, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet 2019;394:1638-1650. https://doi.org/10.1016/S0140-6736(19)31881-1
  98. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, Silverberg JI, Deleuran M, Kataoka Y, Lacour JP, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;375:2335-2348. https://doi.org/10.1056/NEJMoa1610020
  99. Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol 2000;164:2585-2591. https://doi.org/10.4049/jimmunol.164.5.2585
  100. Mentink-Kane MM, Cheever AW, Thompson RW, Hari DM, Kabatereine NB, Vennervald BJ, Ouma JH, Mwatha JK, Jones FM, Donaldson DD, et al. IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci U S A 2004;101:586-590. https://doi.org/10.1073/pnas.0305064101
  101. Rosenberg HF, Dyer KD, Foster PS. Eosinophils: changing perspectives in health and disease. Nat Rev Immunol 2013;13:9-22. https://doi.org/10.1038/nri3341
  102. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017;376:2448-2458. https://doi.org/10.1056/NEJMoa1703501
  103. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, Trevor JL, Magnan A, Ten Brinke A. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med 2017;5:390-400. https://doi.org/10.1016/S2213-2600(17)30125-X
  104. Reiman RM, Thompson RW, Feng CG, Hari D, Knight R, Cheever AW, Rosenberg HF, Wynn TA. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun 2006;74:1471-1479. https://doi.org/10.1128/IAI.74.3.1471-1479.2006
  105. Swartz JM, Dyer KD, Cheever AW, Ramalingam T, Pesnicak L, Domachowske JB, Lee JJ, Lee NA, Foster PS, Wynn TA, et al. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood 2006;108:2420-2427. https://doi.org/10.1182/blood-2006-04-015933