DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8
Year: 2024
Type: article
Abstract: Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the transcription factor Irf8 (interferon regulatory factor 8) induced its re-expression and promoted its repressor activity. As a result, DAC restored joint homeostasis by resetting the transcriptomic signature of negative regulators of inflammation in synovial macrophages (MerTK, Trem2, and Cx3cr1), T REGs (Foxp3), and SFs (Pdpn and Fapα). In conclusion, we found that Irf8 is necessary for the inhibitory effect of DAC in murine arthritis and that direct expression of Irf8 is sufficient to significantly mitigate arthritis.
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Orthopaedic Research and Education Foundation, Shriners Hospitals for Children, National Institutes of Health, National Institute on Aging, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Cabinet microCT System for Musculoskeletal Specimen Imaging, Novel insulin-sensitizing NASH/diabetes drugs., Mechanisms of Physiologic and Pathologic Osteoclastogenesis, Epigenetic Regulation of Chondrogenesis and Cartilage Development, Epigenetic Regulation of Chondrogenesis and Cartilage Development, Role of gasdermin D in bone resorption, Drug target identification using CRISPRi/a screening, G9000230194, RESOURCE BASED CENTER FOR MUSCULOSKELETAL BIOLOGY AND MEDICINE, Regulation of Osteoclastogenesis and Inflammatory Osteolysis, Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis, Molecular pathways of calcium pyrophosphate deposition disease, Diabetes and Related Metabolic Diseases
OpenAlex ID: W4391578331