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

Nat Commun. 2021 Oct 27;12(1):6198. doi: 10.1038/s41467-021-26477-4.


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.

MeSH terms

  • Animals
  • Autoimmunity / drug effects
  • Autoimmunity / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Humans
  • Interleukin-10 / metabolism
  • Janus Kinase 2 / metabolism*
  • Membrane Transport Proteins / deficiency
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Oleanolic Acid / analogs & derivatives
  • Oleanolic Acid / pharmacology
  • Oleanolic Acid / therapeutic use
  • Phosphorylation
  • Protein Binding
  • STAT3 Transcription Factor / metabolism*
  • Saponins / pharmacology
  • Saponins / therapeutic use
  • Signal Transduction


  • Cell Cycle Proteins
  • IL10 protein, mouse
  • Membrane Transport Proteins
  • Optn protein, mouse
  • STAT3 Transcription Factor
  • Saponins
  • Stat3 protein, mouse
  • Interleukin-10
  • Oleanolic Acid
  • Jak2 protein, mouse
  • Janus Kinase 2
  • saikosaponin D