DNA methylation governs the dynamic regulation of inflammation by apoptotic cells during efferocytosis.
Efficient clearance of apoptotic cells (AC) is pivotal in preventing autoimmunity and is a potent immunosuppressive stimulus. However, activation of cells prior to apoptosis abolishes their immunoregulatory properties. Here we show using the antigen-induced model of arthritis that the degree of DNA methylation within AC confers their immunomodulatory plasticity. DNA isolated from resting and activated AC mimicked their respective immune effects. Demethylation of DNA abrogated the protective effect of AC whereas remethylation of AC DNA reversed the effects of activation and restored the ability to inhibit inflammation. Disease suppression or lack thereof was associated with TGFβ and IL-6 production respectively. Apoptotic CD4+T cells from patients with rheumatoid arthritis and systemic lupus erythematosus were demethylated compared to healthy controls and favoured production of IL-6 when cultured with healthy macrophages, in contrast to the TGFβ produced in response to healthy AC. Our data implicate AC DNA methylation as the molecular switch that imprints their regulatory properties.
Centre for Rheumatology, Division of Medicine, University College London, WC1E 6JF London, UK.
Clare A
CA
Notley
Centre for Rheumatology, Division of Medicine, University College London, WC1E 6JF London, UK.
Christine K
CK
Jordan
Centre for Rheumatology, Division of Medicine, University College London, WC1E 6JF London, UK.
Jenny L
JL
McGovern
Centre for Rheumatology, Division of Medicine, University College London, WC1E 6JF London, UK.
Mark A
MA
Brown
Centre for Rheumatology, Division of Medicine, University College London, WC1E 6JF London, UK.
Michael R
MR
Ehrenstein
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004247:DNA / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000187:drug effects; D061251:Primary Cell Culture; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D012710:Serum Albumin, Bovine; D004247:DNA