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

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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Main Authors: 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
Format: Article
Language:English
Published: Springer Nature 2025-05-01
Series:EMBO Molecular Medicine
Subjects:
IL-36 Signaling
Crohn’s Disease
Personalized Therapy
Genetics
Online Access:https://doi.org/10.1038/s44321-025-00245-z
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Summary: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.
ISSN:1757-4684

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