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

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. Optineurin (OPTN) has been implicated in various biological processes, but its function in dendritic cells (DC) maturation is still unclear. Here the authors show, by characterizing Optn-conditional knockout mice, that the loss of OPTN induces Jak2/Stat3 activation and IL-10 production to suppress DC maturation and function, thereby ameliorating autoimmune responses in mice.

Automated summary

Optineurin (OPTN) plays a crucial role in regulating dendritic cell (DC) maturation, where its deficiency leads to Jak2/Stat3 activation and IL-10 production, suppressing DC maturation and function to ameliorate autoimmune responses in mice.