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Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling

Author

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  • Jiajia Wang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Jiaying Wang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Wenxiang Hong

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Lulu Zhang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Liqian Song

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Qi Shi

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Yanfei Shao

    (People’s Hospital of Hangzhou Medical College)

  • Guifeng Hao

    (People’s Hospital of Hangzhou Medical College)

  • Chunyan Fang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Yueping Qiu

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Lijun Yang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Zhaoxu Yang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Jincheng Wang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Ji Cao

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Bo Yang

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Qiaojun He

    (College of Pharmaceutical Sciences, Zhejiang University)

  • Qinjie Weng

    (College of Pharmaceutical Sciences, Zhejiang University)

Abstract

Optineurin (OPTN) has important functions in diverse biological processes and diseases, but its effect on dendritic cell (DC) differentiation and functionality remains elusive. Here we show that OPTN is upregulated in human and mouse DC maturation, and that deletion of Optn in mice via CD11c-Cre attenuates DC maturation and impairs the priming of CD4+ T cells, thus ameliorating autoimmune symptoms such as experimental autoimmune encephalomyelitis (EAE). Mechanistically, OPTN binds to the JH1 domain of JAK2 and inhibits JAK2 dimerization and phosphorylation, thereby preventing JAK2-STAT3 interaction and inhibiting STAT3 phosphorylation to suppress downstream transcription of IL-10. Without such a negative regulation, Optn-deficient DCs eventually induce an IL-10/JAK2/STAT3/IL-10 positive feedback loop to suppress DC maturation. Finally, the natural product, Saikosaponin D, is identified as an OPTN inhibitor, effectively inhibiting the immune-stimulatory function of DCs and the disease progression of EAE in mice. Our findings thus highlight a pivotal function of OPTN for the regulation of DC functions and autoimmune disorders.

Suggested Citation

  • Jiajia Wang & Jiaying Wang & Wenxiang Hong & Lulu Zhang & Liqian Song & Qi Shi & Yanfei Shao & Guifeng Hao & Chunyan Fang & Yueping Qiu & Lijun Yang & Zhaoxu Yang & Jincheng Wang & Ji Cao & Bo Yang & , 2021. "Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26477-4
    DOI: 10.1038/s41467-021-26477-4
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    References listed on IDEAS

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    1. Takaho A. Endo & Masaaki Masuhara & Masahiro Yokouchi & Ritsu Suzuki & Hiroshi Sakamoto & Kaoru Mitsui & Akira Matsumoto & Shyu Tanimura & Motoaki Ohtsubo & Hiroyuki Misawa & Tadaaki Miyazaki & Noguei, 1997. "A new protein containing an SH2 domain that inhibits JAK kinases," Nature, Nature, vol. 387(6636), pages 921-924, June.
    2. Xingrong Du & Jing Wen & Yanyan Wang & Peer W. F. Karmaus & Alireza Khatamian & Haiyan Tan & Yuxin Li & Cliff Guy & Thanh-Long M. Nguyen & Yogesh Dhungana & Geoffrey Neale & Junmin Peng & Jiyang Yu & , 2018. "Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells," Nature, Nature, vol. 558(7708), pages 141-145, June.
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