Indirect inhibition of the NLRP3-interleukin-1β axis contributes to the efficacy of JAK1 inhibitors in experimental colitis and human ulcerative colitis
Abstract
Abstract 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.
Article Details
Authors (33)
Beibei Liu
Institute for Astronomy
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