IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations
Abstract The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. We here identified four Crohn’s disease p...
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Springer Nature
2025-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00245-z |
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| author | Julia Hecker Christina Plattner Camila A Cancino Britt-Sabina Löscher Judith Saurenbach Marilena Letizia Dietmar Rieder TRR241 IBDome Consortium Inka Freise Kristina Koop Clemens Neufert Désirée Kunkel Zainab Al Khatim Lars-Arne Schaafs Anja Schütz Christoph Becker Raja Atreya Zlatko Trajanoski Andre Franke Elena Sonnenberg Ahmed N Hegazy Britta Siegmund Carl Weidinger |
| author_facet | Julia Hecker Christina Plattner Camila A Cancino Britt-Sabina Löscher Judith Saurenbach Marilena Letizia Dietmar Rieder TRR241 IBDome Consortium Inka Freise Kristina Koop Clemens Neufert Désirée Kunkel Zainab Al Khatim Lars-Arne Schaafs Anja Schütz Christoph Becker Raja Atreya Zlatko Trajanoski Andre Franke Elena Sonnenberg Ahmed N Hegazy Britta Siegmund Carl Weidinger |
| author_sort | Julia Hecker |
| collection | DOAJ |
| description | Abstract The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. We here identified four Crohn’s disease patients with heterozygous missense mutations in the IL-36 receptor antagonist (IL36RN, IL-36RA). Experimental overexpression and functional assays demonstrated that two identified mutations resulted in reduced expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn’s disease in a subset of patients and that inhibiting IL-36 signaling could offer a personalized therapeutic approach for these patients. |
| format | Article |
| id | doaj-art-e688a17418c8430caa7e4217cb01ab3a |
| institution | DOAJ |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e688a17418c8430caa7e4217cb01ab3a2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46842025-05-011771539155510.1038/s44321-025-00245-zIL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutationsJulia Hecker0Christina Plattner1Camila A Cancino2Britt-Sabina Löscher3Judith Saurenbach4Marilena Letizia5Dietmar Rieder6TRR241 IBDome ConsortiumInka Freise7Kristina Koop8Clemens Neufert9Désirée Kunkel10Zainab Al Khatim11Lars-Arne Schaafs12Anja Schütz13Christoph Becker14Raja Atreya15Zlatko Trajanoski16Andre Franke17Elena Sonnenberg18Ahmed N Hegazy19Britta Siegmund20Carl Weidinger21Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinBiocenter, Institute of Bioinformatics, Medical University of InnsbruckDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinInstitute of Clinical Molecular Biology, Kiel University and University Medical CenterDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinBiocenter, Institute of Bioinformatics, Medical University of InnsbruckDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinDepartment of Medicine 1, Friedrich-Alexander-Universität Erlangen-NürnbergDepartment of Medicine 1, Friedrich-Alexander-Universität Erlangen-NürnbergBerlin Institute of Health at Charité - Universitätsmedizin Berlin, Flow & Mass Cytometry Core FacilityDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinDepartment of Radiology, Charité - Universitätsmedizin BerlinMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-NürnbergDepartment of Medicine 1, Friedrich-Alexander-Universität Erlangen-NürnbergBiocenter, Institute of Bioinformatics, Medical University of InnsbruckInstitute of Clinical Molecular Biology, Kiel University and University Medical CenterDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinDepartment of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin FranklinAbstract The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. We here identified four Crohn’s disease patients with heterozygous missense mutations in the IL-36 receptor antagonist (IL36RN, IL-36RA). Experimental overexpression and functional assays demonstrated that two identified mutations resulted in reduced expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn’s disease in a subset of patients and that inhibiting IL-36 signaling could offer a personalized therapeutic approach for these patients.https://doi.org/10.1038/s44321-025-00245-zIL-36 SignalingCrohn’s DiseasePersonalized TherapyGenetics |
| spellingShingle | Julia Hecker Christina Plattner Camila A Cancino Britt-Sabina Löscher Judith Saurenbach Marilena Letizia Dietmar Rieder TRR241 IBDome Consortium Inka Freise Kristina Koop Clemens Neufert Désirée Kunkel Zainab Al Khatim Lars-Arne Schaafs Anja Schütz Christoph Becker Raja Atreya Zlatko Trajanoski Andre Franke Elena Sonnenberg Ahmed N Hegazy Britta Siegmund Carl Weidinger IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations EMBO Molecular Medicine IL-36 Signaling Crohn’s Disease Personalized Therapy Genetics |
| title | IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations |
| title_full | IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations |
| title_fullStr | IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations |
| title_full_unstemmed | IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations |
| title_short | IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations |
| title_sort | il 36 signaling as a drug target in crohn s disease patients with il36rn mutations |
| topic | IL-36 Signaling Crohn’s Disease Personalized Therapy Genetics |
| url | https://doi.org/10.1038/s44321-025-00245-z |
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