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

Journal article
Authors Beatrice Bergström
Christina Lundqvist
Georgios Vasileiadis
Hans Carlsten
Olov Ekwall
Anna-Karin H Ekwall
Published in Frontiers in Immunology
Volume 10
ISSN 1664-3224
Publication year 2019
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Centre for Bone and Arthritis Research
Institute of Clinical Sciences, Department of Pediatrics
Language en
Links dx.doi.org/10.3389/fimmu.2019.01384
Keywords rheumatoid arthritis, fibroblast-like synoviocytes, inflammation, cytokines, AIRE, interferon response, DNA methylation, expression, cells, association, invasion, cxcl10, Immunology
Subject categories Immunology in the medical area

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-1 beta by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-gamma 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.

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