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<p>Tofacitinib, a pan–Janus kinase inhibitor, and the Janus kinase 1–preferential inhibitors Upadacitinib and Filgotinib are approved for the treatment of ulcerative colitis, yet their molecular mechanisms of action remain incompletely understood. Here, using dextran sulfate sodium–induced and T cell transfer colitis models together with analyses of individuals with ulcerative colitis, we show that all three inhibitors ameliorate colitis in mice with macrophage-specific deletion of protein tyrosine phosphatase non-receptor type 2, a model characterized by hyperactive Janus kinase–signal transducer and activator of transcription signaling. In contrast, only Upadacitinib and Filgotinib provide enhanced protection in wild-type mice – an effect that is lost upon genetic disruption of inflammasome signaling. Longitudinal single-cell transcriptomic analyses and immunostaining of intestinal biopsies further show that Upadacitinib reduces interleukin-1β expression in vivo, which associates with clinical response. Thus, indirect suppression of inflammasome activity contributes to the efficacy of Janus kinase 1–preferential inhibitors.</p>

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Indirect inhibition of the NLRP3-interleukin-1β axis contributes to the efficacy of JAK1 inhibitors in experimental colitis and human ulcerative colitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Beibei Liu,
  • Marianne R. Spalinger,
  • Annalisa Invernizzi,
  • Eike Gerdes,
  • Babett Steglich,
  • Marlene Schwarzfischer,
  • Andres Machicote,
  • Penelope Pelczar,
  • Doris Pöhlmann,
  • Mikolaj Nawrocki,
  • Marius Böttcher,
  • Ayob Aleko,
  • Lis Noelia Velasquez,
  • Sandra Wende,
  • Franziska Stallbaum,
  • Justus Neuendorff,
  • Saskia Grosshauser,
  • Franziska Muscate,
  • Gemma Douilhet,
  • Laura Garcia Perez,
  • Morsal Sabihi,
  • Katharina Möller,
  • Florian Viehweger,
  • Jan P. Sutter,
  • Christoph Kilian,
  • Yogesh Kumar,
  • Thorben Fründt,
  • Guido Sauter,
  • Thomas Rösch,
  • Nicola Gagliani,
  • Amedeo Caflisch,
  • Michael Scharl,
  • Samuel Huber

摘要

Tofacitinib, a pan–Janus kinase inhibitor, and the Janus kinase 1–preferential inhibitors Upadacitinib and Filgotinib are approved for the treatment of ulcerative colitis, yet their molecular mechanisms of action remain incompletely understood. Here, using dextran sulfate sodium–induced and T cell transfer colitis models together with analyses of individuals with ulcerative colitis, we show that all three inhibitors ameliorate colitis in mice with macrophage-specific deletion of protein tyrosine phosphatase non-receptor type 2, a model characterized by hyperactive Janus kinase–signal transducer and activator of transcription signaling. In contrast, only Upadacitinib and Filgotinib provide enhanced protection in wild-type mice – an effect that is lost upon genetic disruption of inflammasome signaling. Longitudinal single-cell transcriptomic analyses and immunostaining of intestinal biopsies further show that Upadacitinib reduces interleukin-1β expression in vivo, which associates with clinical response. Thus, indirect suppression of inflammasome activity contributes to the efficacy of Janus kinase 1–preferential inhibitors.