Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity

  • Immunity. 2024 Jun 17:S1074-7613(24)00279-6. doi: 10.1016/j.immuni.2024.05.025.
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
Affiliations
  • 1. Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Frontiers Research Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 2. Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 3. Frontiers Research Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 4. Institute of Materia Medical, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 5. National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China.
  • 6. Department of Rheumatology, Beijing Hospital, Beijing 100730, China.
  • 7. Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China.
  • 8. CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
  • 9. Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Frontiers Research Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China; National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China. Electronic address: [email protected].
PMID: 38908373 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.

Keywords
JAK1; autoimmunity; autoinflammation; cytokine signaling; spermine; type I interferon.
Products