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

Jiajia Wang,Chunyan Fang,Lulu Zhang,Yueping Qiu,Qinjie Weng,Yanfei Shao,Bo Yang,Jiaying Wang,Liqian Song,Guifeng Hao,Jincheng Wang,Ji Cao,Wenxiang Hong,Qiaojun He,Lijun Yang,Qi Shi,Zhaoxu Yang

doi:10.1038/s41467-021-26477-4

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.

Highlights

Optineurin (OPTN) has important functions in diverse biological processes and diseases, but its effect on dendritic cell (DC) differentiation and functionality remains elusive
Array analysis showed that Optn gene expression was significantly increased in mature monocyte-derived dendritic cells (MoDCs), similar as the dramatically upregulated DC maturation-related genes, such as CD40, tumor necrosis factor (TNF), IL-1B, CXCL9, and CXCL10 (Fig. 1a)
Be different from the common GM-CSF (20 ng/ml) and IL-4 (5 ng/ml) system that comprised both of DCs and macrophages[15], our system acquired quite a low number of CD11c+major histocompatibility complex (MHC)-II-CD11bhigh cells and almost no CD115+ macrophages (Supplementary Fig. 1), representing an effective bone marrow-derived dendritic cells (BMDCs) culture system in vitro

Summary

Introduction

Optineurin (OPTN) has important functions in diverse biological processes and diseases, but its effect on dendritic cell (DC) differentiation and functionality remains elusive. 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/IL10 positive feedback loop to suppress DC maturation. 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. The production of type I IFNs in the host defense against infections required the interaction between ubiquitin chains and OPTN13 It remains elusive whether OPTN plays a specific role during DC maturation and mediates the immune system. The natural product, Saikosaponin D (SSD), attenuates EAE symptom by inhibiting OPTN expression, suggesting that interfering OPTN could be beneficial for the therapeutic treatment of autoimmune diseases

Methods

Results

Conclusion