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PGE2 Enhances Human ILC3 Function but Constrains ILC2-to-ILC3 Plasticity.

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Title: PGE2 Enhances Human ILC3 Function but Constrains ILC2-to-ILC3 Plasticity.
Authors: Wirth L; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.; Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.; Clinical Lung- and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Weigel W; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.; Clinical Lung- and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Kokkinou E; Department of Oncology, Bloomberg Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Kolmert J; Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Johnsson AK; Division of Immunology and Allergy, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden., Quaranta A; Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Wheelock C; Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden., Jangard M; ENT Unit, Sophiahemmet University and Sophiahemmet Hospital, Stockholm, Sweden., Pandey RV; Department of Dermatology, Medical University of Vienna, Vienna, Austria., Dahlén SE; Clinical Lung- and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden., Tibbitt CA; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.; Clinical Lung- and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Hochdörfer T; Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Mjösberg J; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.; Clinical Lung- and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Source: European journal of immunology [Eur J Immunol] 2026 Oct; Vol. 56 (10), pp. e70296.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 1273201 Publication Model: Print Cited Medium: Internet ISSN: 1521-4141 (Electronic) Linking ISSN: 00142980 NLM ISO Abbreviation: Eur J Immunol Subsets: MEDLINE
Imprint Name(s): Publication: <2005->: Weinheim : Wiley-VCH
Original Publication: Weinheim, Verlag Chemie GmbH.
MeSH Terms: Dinoprostone*/immunology , Dinoprostone*/metabolism , Lymphocytes*/immunology , Immunity, Innate*/immunology , Cell Plasticity*/immunology , Asthma*/immunology, Prostaglandin D2/metabolism ; Humans ; Cells, Cultured
Abstract: Type 2 innate lymphoid cells (ILC2) drive eosinophilic asthma, whereas ILC3 and plastic ILC2/3 states are implicated in neutrophilic and mixed granulocytic disease endotypes. While lipid mediators regulate ILC2 function and airway inflammation, their role in human ILC3 biology and ILC plasticity remains poorly defined. We investigated how eicosanoid biosynthesis and signalling regulate human ILC2 and ILC3 function across canonical and plastic states. Here, we identified distinct prostaglandin (PG) profiles across ILC subsets. Unlike ILC2, which produce and rely on PGD2, ILC3 produced PGE2, which stimulated their release of IL-17F and IL-22. ILC2-to-ILC3 plasticity induced a biosynthetic switch towards PGE2 production that correlated with IL-17A and IL-17F expression. However, subset-intrinsic prostaglandin responses were preserved: hybrid ILC2/3 phenotypes, unlike bona fide ILC3, remained susceptible to PGE2-mediated inhibition, indicating a key functional distinction between these populations.Collectively, our data identify PGE2 as a central regulator of ILC3 function, paralleling the role of PGD2 in ILC2. These findings position PGs as key orchestrators of ILC subset function and plasticity and provide mechanistic insights into the regulation of ILC3 and hybrid ILC2/3 phenotypes associated with neutrophilic and mixed granulocytic asthma.
(© 2026 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)
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Grant Information: European Union's Horizon 2020 research and innovation
Contributed Indexing: Keywords: ILC2; ILC3; PGE2; plasticity; prostaglandins
Substance Nomenclature: K7Q1JQR04M (Dinoprostone)
RXY07S6CZ2 (Prostaglandin D2)
Entry Date(s): Date Created: 20261008 Date Completed: 20261008 Latest Revision: 20261026
Update Code: 20261026
PubMed Central ID: PMC13647482
DOI: 10.1002/eji.70296
PMID: 42847415
Database: MEDLINE
Description
ISSN:1521-4141
DOI:10.1002/eji.70296