Abstract
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.
Highlights
Efficient clearance of apoptotic cells (AC) is pivotal in preventing autoimmunity and is a potent immunosuppressive stimulus
We reported that intravenous administration of apoptotic dendritic cells (DC) which had been activated with LPS prior to induction of apoptosis were unable to suppress inflammatory arthritis due to a surge in splenic IL-6 from resident splenic cells which blocked TGFβproduction, in contrast to apoptotic DC not exposed to LPS8
We have previously shown that LPS activation of dendritic cells (DC) prior to apoptosis induction abolishes their ability to suppress antigen-induced arthritis (AIA) compared to unstimulated apoptotic DC8
Summary
Efficient clearance of apoptotic cells (AC) is pivotal in preventing autoimmunity and is a potent immunosuppressive stimulus. Activation of cells prior to apoptosis abolishes their immunoregulatory properties. Macrophages as one of the archetypal professional phagocytes contribute to maintaining an immunosuppressive environment during the engulfment of AC via inhibition of pro-inflammatory cytokines whilst maintaining or increasing production of immunoregulatory cytokines such as TGFβ3–5. Less is known of the processes by which AC lose their ability to mediate inhibition of inflammation TLR ligands have been implicated in subverting the immunoregulatory response to AC7. DNA can have pro-inflammatory effects[11] and we investigated whether alterations in apoptotic DNA could account for the distinct immune effects of resting and activated AC.
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