Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8. Proc Natl Acad Sci U S A 2024 Feb 13;121(7):e2310264121

Date

02/06/2024

Pubmed ID

38319963

Pubmed Central ID

PMC10873594

DOI

10.1073/pnas.2310264121

Scopus ID

2-s2.0-85184532962 (requires institutional sign-in at Scopus site)   1 Citation

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), TREGs (Foxp3), and SFs (Pdpn and FapĪ±). 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.

Author List

Swarnkar G, Semenkovich NP, Arra M, Mims DK, Naqvi SK, Peterson T, Mbalaviele G, Wu CL, Abu-Amer Y

Author

Nicholas Semenkovich MD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Anti-Inflammatory Agents
Arthritis
Azacitidine
DNA Methylation
Epigenesis, Genetic
Inflammation
Interferon Regulatory Factors
Membrane Glycoproteins
Mice
Receptors, Immunologic