{Reference Type}: Journal Article
{Title}: Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity.
{Author}: Xu H;Zhang X;Wang X;Li B;Yu H;Quan Y;Jiang Y;You Y;Wang Y;Wen M;Liu J;Wang M;Zhang B;Li Y;Zhang X;Lu Q;Yu CY;Cao X;
{Journal}: Immunity
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 17
{Factor}: 43.474
{DOI}: 10.1016/j.immuni.2024.05.025
{Abstract}: Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-β-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.