DNA Hypomethylation Ameliorates Erosive Inflammatory Arthritis by Modulating Interferon Regulatory Factor-8

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2024 Feb 6

PMID 38319963

Authors

Gaurav Swarnkar

Nicholas P Semenkovich

Manoj Arra

Dorothy K Mims

Syeda Kanwal Naqvi

Timothy Peterson

Gabriel Mbalaviele

Chia-Lung Wu

Yousef Abu-Amer

Affiliations

Soon will be listed here.

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 (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.

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DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8.

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PMID: 38319963 PMC: 10873594. DOI: 10.1073/pnas.2310264121.

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