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<p>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 (<i>IL36RN</i>, 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 <i>IL36RN</i>-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 <i>IL36RN</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月30日

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  • Julia Hecker,
  • Christina Plattner,
  • Camila A Cancino,
  • Britt-Sabina Löscher,
  • Judith Saurenbach,
  • Marilena Letizia,
  • Dietmar Rieder,
  • 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

摘要

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.