Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity

Henan Xu 1, Xiao Zhang 2, Xin Wang 2, Bo Li 3, Hang Yu 4, Yuan Quan 2, Yan Jiang 2, Yuling You 2, Yan Wang 4, Mingyue Wen 2, Juan Liu 5, Min Wang 6, Bo Zhang 7, Yixian Li 8, Xuan Zhang 6, Qianjin Lu 7, Chu-Yi Yu 8, Xuetao Cao 9

Immunity. 2024 Jun 17:S1074-7613(24)00279-6. doi: 10.1016/j.immuni.2024.05.025.

PMID: 38908373

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.