Biomaterial Database

BRD3 Regulates the Inflammatory and Stress Response in Rheumatoid Arthritis Synovial Fibroblasts. 2023

Tanja Seifritz, and Matthias Brunner, and Eva Camarillo Retamosa, and Malgorzata Maciukiewicz, and Monika Krošel, and Larissa Moser, and Thomas Züllig, and Matija Tomšič, and Oliver Distler, and Caroline Ospelt, and Kerstin Klein

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.

BACKGROUND Individual functions of members of the bromodomain (BRD) and extra-terminal (BET) protein family underlying the anti-inflammatory effects of BET inhibitors in rheumatoid arthritis (RA) are incompletely understood. Here, we aimed to analyze the regulatory functions of BRD3, an understudied member of the BET protein family, in RA synovial fibroblasts (FLS). METHODS BRD3 was silenced in FLS prior to stimulation with TNF. Alternatively, FLS were treated with I-BET. Transcriptomes were analyzed by RNA sequencing (RNAseq), followed by pathway enrichment analysis. We confirmed results for selective target genes by real-time PCR, ELISA, and Western blotting. RESULTS BRD3 regulates the expression of several cytokines and chemokines in FLS, and positively correlates with inflammatory scores in the RA synovium. In addition, RNAseq pointed to a profound role of BRD3 in regulating FLS proliferation, metabolic adaption, and response to stress, including oxidative stress, and autophagy. CONCLUSIONS BRD3 acts as an upstream regulatory factor that integrates the response to inflammatory stimuli and stress conditions in FLS and executes many functions of BET proteins that have previously been identified using pan-BET inhibitors.