Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Mouse)

Combining metabolomics analyses with an IFN-stimulated response elements reporter system, we identify spermine as a cellular metabolite brake for JAK1 signaling. Spermine directly binds to FERM and SH2 domains of JAK1 to impair IFNAR2-JAK1 interaction. Spermine suppresses JAK1 phosphorylation triggered by types I and II cytokines, including IFN-I/II, IL-2, and IL-6. Spermine treatment attenuates autoimmune pathogenesis in a SLE murine model and reduces IFN-I signaling in monocytes from SLE patients, which have reduced spermine levels. Overall design: 7 weeks old female Ifnar1+/+ or Ifnar1-/- mice were pretreated with spermine or PBS for 3days, then injected with pristane (Sigma-Aldrich) to induce SLE as described. Blood was collected from posterior orbital venous plexus to isolate mRNA for RNA-sequencing.