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

Hecker, J.; Plattner, C.; Cancino, C.A.; Löscher, B.S.; Saurenbach, J.; Letizia, M.; Rieder, D.; Freise, I.; Koop, K.; Neufert, C.; Kunkel, D.; Al Khatim, Z.; Schaafs, L.A.; Schütz, A.; Becker, C.; Atreya, R.; Trajanoski, Z.; Franke, A.; Sonnenberg, E.; Hegazy, A.N.; Siegmund, B.; Weidinger, C.

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

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Item Type:	Article
Title:	IL-36 signaling as a drug target in Crohn's disease patients with IL36RN mutations
Creators Name:	Hecker, J., Plattner, C., Cancino, C.A., Löscher, B.S., Saurenbach, J., Letizia, M., Rieder, D., Freise, I., Koop, K., Neufert, C., Kunkel, D., Al Khatim, Z., Schaafs, L.A., Schütz, A., Becker, C., Atreya, R., Trajanoski, Z., Franke, A., Sonnenberg, E., Hegazy, A.N., Siegmund, B. and Weidinger, C.
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.
Keywords:	IL-36 Signaling, Crohn’s Disease, Personalized Therapy, Genetics
Source:	EMBO Molecular Medicine
ISSN:	1757-4676
Publisher:	EMBO Press / Wiley
Volume:	17
Number:	7
Page Range:	1539-1555
Date:	11 July 2025
Additional Information:	Leif S.-H. Ludwig and Ashley Sanders are members of the TRR241 IBDome Consortium.
Official Publication:	https://doi.org/10.1038/s44321-025-00245-z
PubMed:	View item in PubMed

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