The Rheumatoid Arthritis Risk Gene AIRE Is Induced by Cytokines in Fibroblast-Like Synoviocytes and Augments the Pro-inflammatory Response

Abstract

The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of AIRE have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1β by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-γ regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

“…The pathogenic role of IFN-c as an upstream regulator in RA synovium has also been shown by meta-analysis across datasets of gene expression microarray [24]. Another recent study by Bergstr€ om et al [25] has demonstrated a novel role for the autoimmune regulator (AIRE), a master regulator of T cell tolerance in the thymus, in IFN-c signature in synovial fibroblasts. By RNA sequencing, they identified 3,492 differentially expressed genes, including AIRE, in synovial fibroblasts following treatment with TNF-a and IL-1b.…”

Metformin, an AMPK Activator, Inhibits Activation of FLSs but Promotes HAPLN1 Secretion

“…In this context, fibroblast-like synoviocytes (FLSs) are increasingly recognized as key effector cells. 3 The activated FLSs are hyperproliferative and resistant to apoptosis with an increased capacity for migration, causing pannus formation and destruction of joint cartilage. Production of inflammatory factors such as tumor necrosis factor a (TNF-a) and interleukin 17 (IL-17), chemokines, and matrix-degrading molecules by FLSs contributes to their invasiveness.…”

Bridging Insights From Lymph Node and Synovium Studies in Early Rheumatoid Arthritis

“…RNA sequencing revealed that AIRE did not induce PTAs in FLS, but stimulates pro-inflammatory cytokine and chemokine secretion associated with RA development. AIRE expression was hardly detected on mRNA level in unstimulated RA FLS, but largely increased and detected at protein level after TNFα and IL1β stimulation (64). Single-cell RNA sequencing on RA FLS showed a putative subpopulation of CD90 + HLA-DR high FLS expanded in the sublining of RA synovium.…”

“…Similar to stromal cells in the LN, FLS create a pro-survival and anti-apoptotic microenvironment in the synovium by secreting cytokines and chemokines that support the survival of immune cells supporting inflammation (62,63). AIRE was recently identified as a cytokine-induced RA-risk gene in RA FLS (64). RNA sequencing revealed that AIRE did not induce PTAs in FLS, but stimulates pro-inflammatory cytokine and chemokine secretion associated with RA development.…”