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

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.