IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations

Hecker J, Plattner C, Cancino CA, Löscher BS, Saurenbach J, Letizia M, Rieder D, Freise I, Koop K, Neufert C, Kunkel D, Al Khatim Z, Schaafs LA, Schütz A, Becker C, Atreya R, Trajanoski Z, Franke A, Sonnenberg E, Hegazy AN, Siegmund B, Weidinger C (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Embo Molecular Medicine Wiley-VCH Verlag / Wiley Open Access

Book Volume: 17

Pages Range: 1539-1555

Journal Issue: 7

DOI: 10.1038/s44321-025-00245-z

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.

Authors with CRIS profile

Kristina Koop Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Clemens Neufert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Christoph Becker Professur für Molekulare Gastroenterologie Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft / Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) DE Germany (DE)

How to cite

APA:

Hecker, J., Plattner, C., Cancino, C.A., Löscher, B.-S., Saurenbach, J., Letizia, M.,... Weidinger, C. (2025). IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations. Embo Molecular Medicine, 17(7), 1539-1555. https://doi.org/10.1038/s44321-025-00245-z

MLA:

Hecker, Julia, et al. "IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations." Embo Molecular Medicine 17.7 (2025): 1539-1555.

BibTeX: Download