2. Academic Validation
  3. Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity

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

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: caoxt@immunol.org.
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.

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