{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:22:48Z","timestamp":1787667768433,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Severe asthma is characterized by persistent airway inflammation, irreversible airway remodeling, and reduced responsiveness to glucocorticoids. Subepithelial fibrosis, a major determinant of progressive lung function decline, remains mechanistically undefined. Evidence identifies group 2 innate lymphoid cells (ILC2s) as key contributors to fibrotic airway remodeling. Importantly, ILC2s in severe asthma are not simply increased in number but functionally reprogrammed into a pathogenic, profibrotic state. We summarize evidence for pathogenic ILC2s and discuss three defining properties distinguishing them from homeostatic ILC2s. First, pathogenic ILC2s acquire a fibrogenic phenotype marked by increased IL-13, IL-4, IL-5, and amphiregulin, promoting fibroblast activation and matrix deposition. Second, they exhibit enhanced proliferative capacity driven by cell cycle-related (CDK4\/6) and transcriptional (CDK8\/19) cyclin-dependent kinases, expanding the pathogenic pool. Third, JAK\u2013STAT5\u2013Bcl-xL and PI3K\u2013Akt\u2013mTORC1 signaling confers resistance to glucocorticoid-induced apoptosis, enabling persistence despite corticosteroid therapy. Together, these properties provide a mechanistic framework linking chronic type 2 inflammation to persistent airway fibrosis. We also discuss therapeutic strategies targeting alarmins, cytokines, CDKs, and steroid-resistance signaling, and highlight open questions on ILC2 heterogeneity. Future single-cell and spatial transcriptomic studies will determine whether these properties arise within a common ILC2 population or distinct subsets, informing precision therapies for severe asthma.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1957593","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:32:50Z","timestamp":1787664770000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenic group 2 innate lymphoid cells as drivers of lung fibrosis in severe asthma"],"prefix":"10.3389","volume":"17","author":[{"given":"Masaya","family":"Matsuda","sequence":"first","affiliation":[{"name":"Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Sannomiya","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Kaminuma","sequence":"additional","affiliation":[{"name":"Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University","place":["Hiroshima, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nabe","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(24)00383-7","article-title":"Asthma: epidemiology, risk factors, and opportunities for prevention and treatment","volume":"13","author":"Jayasooriya","year":"2025","journal-title":"Lancet Respir Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41533-025-00425-x","article-title":"BTS\/NICE\/SIGN guideline for asthma 2024: Diagnosis, monitoring and chronic asthma management. How does this compare to GINA 2024","volume":"35","author":"Gruffydd-Jones","year":"2025","journal-title":"NPJ Prim Care Respir Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.anai.2019.08.462","article-title":"Evaluating direct costs and productivity losses of patients with asthma receiving GINA 4\/5 therapy in the United States","volume":"123","author":"Settipane","year":"2019","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.18553\/jmcp.2023.29.7.825","article-title":"Incremental cost burden among patients with severe uncontrolled asthma in the United States","volume":"29","author":"Burnette","year":"2023","journal-title":"J Manag Care Spec Pharm"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221212","article-title":"Type 2 inflammation and biological therapies in asthma: Targeted medicine taking flight","volume":"220","author":"Howell","year":"2023","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2301619","DOI":"10.1183\/13993003.01619-2023","article-title":"Airway remodelling in asthma and the epithelium: on the edge of a new era","volume":"63","author":"Varricchi","year":"2024","journal-title":"Eur Respir J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/all.16382","article-title":"Biologics and airway remodeling in asthma: early, late, and potential preventive effects","volume":"80","author":"Varricchi","year":"2025","journal-title":"Allergy"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/imr.70010","article-title":"Chronic inflammation in asthma: Looking beyond the Th2 cell","volume":"330","author":"Olsthoorn","year":"2025","journal-title":"Immunol Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abc9934","article-title":"BATF promotes group 2 innate lymphoid cell-mediated lung tissue protection during acute respiratory virus infection","volume":"7","author":"Wu","year":"2022","journal-title":"Sci Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.immuni.2018.04.023","article-title":"Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosinophils to secrete osteopontin and facilitate airway fibrosis","volume":"49","author":"Morimoto","year":"2018","journal-title":"Immunity"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2026.107143","article-title":"Molecular requirements of pathogenic Th2 cell differentiation in allergic airway disease","volume":"279","author":"Khan","year":"2026","journal-title":"Immunol Lett"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174732","article-title":"Pathogenic changes in group 2 innate lymphoid cells (ILC2s) in a steroid-insensitive asthma model of mice","volume":"916","author":"Matsuda","year":"2022","journal-title":"Eur J Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s41467-025-66683-y","article-title":"mTORC1 signaling in group 2 innate lymphoid cells coordinates neuro-immune crosstalk in allergic lung inflammation","volume":"17","author":"Wang","year":"2025","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ado6649","article-title":"A population of c-kit+ IL-17A+ ILC2s in sputum from individuals with severe asthma supports ILC2 to ILC3 trans-differentiation","volume":"17","author":"Ju","year":"2025","journal-title":"Sci Transl Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1509070112","article-title":"IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions","volume":"112","author":"Monticelli","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B16","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.immuni.2019.02.002","article-title":"Adventitial stromal cells define group 2 innate lymphoid cell tissue niches","volume":"50","author":"Dahlgren","year":"2019","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801285R","article-title":"IL-13 signaling through IL-13 receptor \u03b12 mediates airway epithelial wound repair","volume":"33","author":"Yang","year":"2019","journal-title":"FASEB J"},{"key":"B18","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jaci.2015.05.037","article-title":"Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia","volume":"137","author":"Smith","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b23-00768","article-title":"Steroid-insensitive gene expression of extracellular matrix components and pro-fibrotic factors in the lung associated with airway hyperresponsiveness in murine asthma","volume":"47","author":"Shimora","year":"2024","journal-title":"Biol Pharm Bull"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.06.016","article-title":"MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion","volume":"41","author":"Oliphant","year":"2014","journal-title":"Immunity"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07746-w","article-title":"ILC2-derived LIF licences progress from tissue to systemic immunity","volume":"632","author":"Gogoi","year":"2024","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nri3365","article-title":"Innate lymphoid cells--a proposal for uniform nomenclature","volume":"13","author":"Spits","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/nri3349","article-title":"Innate lymphoid cells--how did we miss them","volume":"13","author":"Walker","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/jimmun\/vkaf171","article-title":"Cyclin-dependent kinase (CDK) 8 and its paralog CDK19 develop group 2 innate lymphoid cell-related lung fibrosis by activating STAT5","volume":"214","author":"Matsuda","year":"2025","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"8120","DOI":"10.1038\/s41467-023-43336-6","article-title":"Activation of ILC2s through constitutive IFN\u03b3 signaling reduction leads to spontaneous pulmonary fibrosis","volume":"14","author":"Otaki","year":"2023","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1315854111","article-title":"IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis","volume":"111","author":"Hams","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1016\/j.jaci.2014.05.011","article-title":"IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice","volume":"134","author":"Li","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1007\/s12016-025-09045-2","article-title":"Targeting IL-13 and IL-4 in asthma: Therapeutic implications on airway remodeling in severe asthma","volume":"68","author":"Sahnoon","year":"2025","journal-title":"Clin Rev Allergy Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119039","article-title":"IL-13 induces YY1 through the AKT pathway in lung fibroblasts","volume":"10","author":"Guo","year":"2015","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26167678","article-title":"Amphiregulin and fibrosis: Existing evidence and future directions","volume":"26","author":"Sisto","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/5018975","article-title":"ILC2 proliferated by IL-33 stimulation alleviates acute colitis in Rag1-\/- mouse through promoting M2 macrophage polarization","volume":"2020","author":"You","year":"2020","journal-title":"J Immunol Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"19589","DOI":"10.1038\/s41598-023-46237-2","article-title":"IL-4 and IL-13 induce equivalent expression of traditional M2 markers and modulation of reactive oxygen species in human macrophages","volume":"13","author":"Scott","year":"2023","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00597","article-title":"Macrophage and innate lymphoid cell interplay in the genesis of fibrosis","volume":"6","author":"Hams","year":"2015","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41420-024-02247-1","article-title":"Macrophages in organ fibrosis: from pathogenesis to therapeutic targets","volume":"10","author":"Jiang","year":"2024","journal-title":"Cell Death Discov"},{"key":"B35","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.cytogfr.2025.08.003","article-title":"From senescence to scarring: Exploring TGF-\u03b2 signaling in cellular aging, fibrotic remodeling, and pulmonary fibrosis","volume":"86","author":"Bhardwaj","year":"2025","journal-title":"Cytokine Growth Factor Rev"},{"key":"B36","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s11882-026-01274-5","article-title":"The emerging role of Ly6G+Nur77+ lung macrophages in Type-2 allergic inflammation: A comprehensive review on asthma pathogenesis","volume":"26","author":"Mehmood","year":"2026","journal-title":"Curr Allergy Asthma Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.03.048","article-title":"Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production","volume":"132","author":"Doherty","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/resp.14506","article-title":"Severe asthma ILC2s demonstrate enhanced proliferation that is modified by biologics","volume":"28","author":"Malik","year":"2023","journal-title":"Respirology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.jacig.2022.07.007","article-title":"Upregulation of IL-4 receptor signaling pathway in circulating ILC2s from asthma patients","volume":"1","author":"Baba","year":"2022","journal-title":"J Allergy Clin Immunol Glob"},{"key":"B40","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/gb4184","article-title":"Cyclin-dependent kinases","volume":"15","author":"Malumbres","year":"2014","journal-title":"Genome Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpet.2025.103726","article-title":"Inhibition of CDK4\/6 attenuates airway remodeling in a murine severe asthma model by suppressing ILC2 proliferation","volume":"392","author":"Matsuda","year":"2025","journal-title":"J Pharmacol Exp Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2026.107174","article-title":"Roles of group 2 innate lymphoid cells in development of steroid-resistant severe asthma and their therapeutic targets","volume":"280","author":"Matsuda","year":"2026","journal-title":"Immunol Lett"},{"key":"B43","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.jaci.2017.03.032","article-title":"Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin","volume":"141","author":"Liu","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abd3489","article-title":"Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases","volume":"6","author":"van der Ploeg","year":"2021","journal-title":"Sci Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13805","article-title":"Involvement of Janus kinase-dependent Bcl-xL overexpression in steroid resistance of group 2 innate lymphoid cells in asthma","volume":"172","author":"Shimora","year":"2024","journal-title":"Immunology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1038\/ncomms3675","article-title":"Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation","volume":"4","author":"Kabata","year":"2013","journal-title":"Nat Commun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpet.2025.103744","article-title":"Essential roles of mTOR in induction of steroid resistance in group 2 innate lymphoid cells (ILC2s) and severe asthma","volume":"392","author":"Matsuda","year":"2025","journal-title":"J Pharmacol Exp Ther"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1957593\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:32:51Z","timestamp":1787664771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1957593\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2026.1957593"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1957593","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"article-number":"1957593"}}