TonEBP in dendritic cells mediates pro-inflammatory maturation and Th1/Th17 responses

Byeong Jin Ye,Chae Young Lee,Whaseon Lee-Kwon,Jun Ho Lee,Gyu Won Jeong,Hyun Park,Soo Youn Choi,Eun Jin Yoo,Hwan Hee Lee,Hyun Je Kang,Hyug Moo Kwon

doi:10.1038/s41419-020-2632-8

Abstract

Dendritic cells (DCs) are potent antigen-presenting cells that link the innate and adaptive immune responses; as such they play pivotal roles in initiation and progression of rheumatoid arthritis (RA). Here, we report that the tonicity-responsive enhancer-binding protein (TonEBP or NFAT5), a Rel family protein involved in the pathogenesis of autoimmune disease and inflammation, is required for maturation and function of DCs. Myeloid cell-specific TonEBP deletion reduces disease severity in a murine model of collagen-induced arthritis; it also inhibits maturation of DCs and differentiation of pathogenic Th1 and Th17 cells in vivo. Upon stimulation by TLR4, TonEBP promotes surface expression of major histocompatibility complex class II and co-stimulatory molecules via p38 mitogen-activated protein kinase. This is followed by DC-mediated differentiation of pro-inflammatory Th1 and Th17 cells. Taken together, these findings provide mechanistic basis for the pathogenic role of TonEBP in RA and possibly other autoimmune diseases.

Highlights

Dendritic cells (DCs) are professional antigenpresenting cells (APCs) that are uniquely capable of priming naïve T-cells, macrophages and B-cells are able to process and present antigens to T-cells[1]
The blockade of rheumatoid arthritis (RA) development in TonEBPhaplodeficient mice[27,30] led us to examine the role of myeloid Tonicity-responsive enhancer-binding protein (TonEBP) in a mouse model of inflammatory arthritis based on myeloid-specific TonEBP knockout; these mice are referred to as TonEBPfl/fl LysM-cre mice
In myeloid lineage cells (peritoneal macrophages, and bone marrow-derived macrophages (BMDMs) and bone marrow-derived-dendritic cells (BMDCs)) TonEBP levels were dramatically reduced in the TonEBPfl/fl LysM-cre mice compared to their TonEBPfl/fl littermates (Supplementary Fig. 1a) confirming genetic deletion of TONEBP

Summary

Introduction

Dendritic cells (DCs) are professional antigenpresenting cells (APCs) that are uniquely capable of priming naïve T-cells, macrophages and B-cells are able to process and present antigens to T-cells[1]. Evidence from clinical studies and experimental models implicates DCs in the pathogenesis of most autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA)[3]. Because dysregulation of immune cells plays a critical role in RA pathogenesis, its reversal is a major therapeutic goal[6,7]. DCs are emerging as an important cell population that plays a role in RA pathogenesis[9,10,11]. DCs are involved in initiating the disease via production of cytokines and presentation of arthritogenic antigens, which together activate autoreactive Th1 and Th17 cells; it is the latter that cause the damage associated with RA9,10. Data from human patients and murine models of early RA show that DC numbers in joint-draining LNs increase prior to visible histological

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Conclusion