IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations
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.
Authors
- Désirée Kunkel (ORCID: https://orcid.org/0000-0002-0054-955X)
- Christoph Becker (ORCID: https://orcid.org/0000-0002-8385-0785)
- Clemens Neufert
- I Freise
- Anja Schütz (ORCID: https://orcid.org/0000-0002-0606-2574)
- Julia Hecker (ORCID: https://orcid.org/0000-0002-4118-3961)
- Carl Weidinger (ORCID: https://orcid.org/0000-0002-9948-0088)
- Britta Siegmund (ORCID: https://orcid.org/0000-0002-0055-958X)
- Raja Atreya (ORCID: https://orcid.org/0000-0002-8556-8433)
- Christina Plattner (ORCID: https://orcid.org/0000-0002-3217-3278)
- Marilena Letizia (ORCID: https://orcid.org/0000-0002-8039-9415)
- Ahmed N. Hegazy (ORCID: https://orcid.org/0000-0002-2946-8251)
- Dietmar Rieder (ORCID: https://orcid.org/0000-0003-1754-690X)
- Britt-Sabina Löscher (ORCID: https://orcid.org/0000-0001-9022-9017)
- André Franke (ORCID: https://orcid.org/0000-0003-1530-5811)
- Kristina Koop (ORCID: https://orcid.org/0000-0002-1672-7234)
- Zlatko Trajanoski (ORCID: https://orcid.org/0000-0002-0636-7351)
- J Saurenbach
- Elena Sonnenberg (ORCID: https://orcid.org/0000-0002-9513-8816)
- C Cancino
- Zainab Al Khatim
- Lars-Arne Schaafs
Institutions
- Innsbruck Medical University (AT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Universität Innsbruck (AT)
- Max Delbrück Center (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Humboldt-Universität zu Berlin (DE)
- German Rheumatism Research Centre (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1038/s44321-025-00245-z
- Citations
- 1
- Primary Topic
- Whipple's Disease and Interleukins
- Type
- article
- Field-Weighted Citation Impact
- 1.47
Funders
- Eli Lilly and Company
- Pfizer
- Gilead Sciences
- Deutsche Forschungsgemeinschaft
- Austrian Science Fund
- Fritz Thyssen Stiftung