BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages.

Jie Li,Jialing Xiang,Anning Lin,Demin Wang,Qianqian Liang,Yongwei Zheng,Weida Yu,Rui Shao,Weiguo Zou,Hongyan Wang,Liansheng Zhang

doi:10.7554/elife.56309

Abstract

The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad3SA/3SA mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology. Our findings put forward a model in which inactivation of BAD confers the apoptosis resistance on synovial sublining macrophages, thereby contributing to the development of arthritis, suggesting that BAD may be a potential therapeutic target for RA.

Highlights

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that primarily affects diarthrodial joints, characterized by hyperplasia of intimal lining, infiltration of macrophages, and lymphocytes in synovial sublining and joint destruction (Firestein, 2003; McInnes and Schett, 2011)
It has long been thought that the resistance of infiltrating synovial sublining macrophages to apoptosis plays a central role in rheumatoid arthritis (RA) pathogenesis (Bresnihan et al, 2009; Haringman et al, 2005; Udalova et al, 2016)
We found that BAD phosphorylation, indicative of its inactivation, was increased in synovial sublining macrophages in arthritic mice and patients with RA

Summary

Introduction

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that primarily affects diarthrodial joints, characterized by hyperplasia of intimal lining, infiltration of macrophages, and lymphocytes in synovial sublining and joint destruction (Firestein, 2003; McInnes and Schett, 2011). Macrophage is one of the most abundant cell types in RA synovium and different subgroups of synovial macrophages play distinct roles in the development of RA (Udalova et al, 2016). Self-renewing tissue-resident macrophages, which mainly locate in synovial lining layer, have anti-inflammatory function and maintain tissue homeostasis for intra-articular structures (Ambarus et al, 2012; Culemann et al, 2019; Uderhardt et al, 2019). The infiltrating macrophages derived from monocytes, which largely locate in synovial sublining layer in inflamed synovium, are the major

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