Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways

Abstract

ObjectivesAge-associated B cells (ABCs) are a recently identified B cell subset, whose expansion has been increasingly linked to the pathogenesis of autoimmune disorders. This study aimed to investigate whether ABCs are involved in the pathogenesis and underlying mechanisms of rheumatoid arthritis (RA).MethodsABCs were assessed in collagen-induced arthritis (CIA) mice and patients with RA using flow cytometry. Transcriptomic features of RA ABCs were explored using RNA-seq. Primary fibroblast-like synoviocytes (FLS) derived from the synovial tissue of patients with RA were cocultured with ABCs or ABCs-conditioned medium (ABCsCM). IL-6, MMP-1, MMP-3 and MMP-13 levels in the coculture supernatant were detected by ELISA. Signalling pathways related to ABCs-induced FLS activation were examined using western blotting.ResultsIncreased ABCs levels in the blood, spleen and inflammatory joints of CIA mice were observed. Notably, ABCs were elevated in the blood, synovial fluid and synovial tissue of patients with RA and positively correlated with disease activity. RNA-seq revealed upregulated chemotaxis-related genes in RA ABCs compared with those in naive and memory B cells. Coculture of FLS with RA ABCs or ABCsCM led to an active phenotype of FLS, with increased production of IL-6, MMP-1, MMP-3 and MMP-13. Mechanistically, ABCsCM-derived TNF-α promoted the upregulation of interferon-stimulated genes in FLS, with elevated phosphorylation of ERK1/2 and STAT1. Furthermore, blockage of ERK1/2 and Janus Kinase (JAK)-STAT1 pathways inhibited the activation of FLS induced by ABCsCM.ConclusionsOur results suggest that ABCs contribute to the pathogenesis of RA by inducing the activation of FLS via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways.

Age/autoimmunity-associated B cells in inflammatory arthritis: An emerging therapeutic target

“…Recently, by combining mass cytometry and single-cell RNA sequencing analyses, Zhang et al (29) revealed that ABCs were expanded in the synovium of RA patients, suggesting a potential role of ABCs in inflammatory arthritis. Consistently, a recent work in our lab has confirmed the expansion of ABCs both in the peripheral blood and in the synovial tissue of RA patients (30). Our findings demonstrated a distinct transcriptomic feature of RA ABCs, which may impact their ability to migrate into the inflammatory joints, where they induce FLS to an aggressive phenotype and perpetuate synovitis development (30).…”

“…Consistently, a recent work in our lab has confirmed the expansion of ABCs both in the peripheral blood and in the synovial tissue of RA patients (30). Our findings demonstrated a distinct transcriptomic feature of RA ABCs, which may impact their ability to migrate into the inflammatory joints, where they induce FLS to an aggressive phenotype and perpetuate synovitis development (30).…”

“…Despite the diverse nomenclature that has been used to describe these cells (Table 1), ABCs are actually emerging as key players in many pathophysiological settings, raising the possibility that this compartment may represent a common pathway in autoimmune-mediated disorders. While we recognize that the term "ABCs" may not an ideal terminology since they are not associated with age in many disease settings including SLE and RA (22,30), we adopt this nomenclature in our review to encompass ABCs and ABClike populations. This is in line with most recent comprehensive reviews on the subject that focus on different aspects (31,(57)(58)(59).…”

A Smart Nanoreactor Based on an O2-Economized Dual Energy Inhibition Strategy Armed with Dual Multi-stimuli-Responsive “Doorkeepers” for Enhanced CDT/PTT of Rheumatoid Arthritis

“…Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis, progressive articular cartilage erosion, and bone destruction, which is regulated by a complex pathological process involving multiple inflammatory cells. , Nowadays, pathological research has revealed that fibroblast-like synovial (FLS) cells are one of the critical effector cells in RA, and their hyperproliferation and infiltration play a key role in the pathogenesis of RA. , Once RA happens, the two- to three-layer synovial lining would be converted to rheumatoid and pannus-like, which is a hyperplastic structure with a greater amount of stimulated FLS cells and macrophages that stretches into the articular interior, connects to the cartilage surface, and infiltrates and decomposes the cartilage matrix leading to bone loss and joint dysfunction. − Recently, many research reports demonstrate that the activation of FLS cells and subsequent joint injury are closely related to the changes of intracellular energy metabolism. , In RA activated FLS (RA-FLS) cells, the balance of the glucose metabolism is disturbed, which is reflected as the proportion of the glycolysis pathway being obviously higher than that of the oxidative phosphorylation pathway. With the rise of glycolysis and acid resistance, RA-FLS cells are especially sensitive to glucose and highly dependent on glycolysis and have a tenacious vitality advantage, which is the main factor for the rapid proliferation and invasion of inflammatory synovium .…”

“…1,2 Nowadays, pathological research has revealed that fibroblastlike synovial (FLS) cells are one of the critical effector cells in RA, and their hyperproliferation and infiltration play a key role in the pathogenesis of RA. 3,4 Once RA happens, the two-to three-layer synovial lining would be converted to rheumatoid and pannus-like, which is a hyperplastic structure with a greater amount of stimulated FLS cells and macrophages that stretches into the articular interior, connects to the cartilage surface, and infiltrates and decomposes the cartilage matrix leading to bone loss and joint dysfunction. 5−7 Recently, many research reports demonstrate that the activation of FLS cells and subsequent joint injury are closely related to the changes of intracellular energy metabolism.…”