Induction of type I IFN is a physiological immune reaction to apoptotic cell-derived membrane microparticles

• Published in: The Journal of immunology (1950) 2012-08, Vol.189 (4), p.1747-1756
• Main Authors: Schiller, Martin, Parcina, Marijo, Heyder, Petra, Foermer, Sandra, Ostrop, Jenny, Leo, Albrecht, Heeg, Klaus, Herrmann, Martin, Lorenz, Hanns-Martin, Bekeredjian-Ding, Isabelle
• Format: Article
• Language: English
• Subjects: Apoptosis - immunology; Cell Separation; Cell-Derived Microparticles - immunology; Dendritic Cells - immunology; Dendritic Cells - secretion; DNA - immunology; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Interferon Type I - immunology; Interferon Type I - secretion; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100631

Membrane microparticles (MMP) released from apoptotic cells deliver signals that secure the anti-inflammatory response beyond the nearest proximity of the apoptotic cell. Plasmacytoid dendritic cells (pDC) are sentinels prepared to detect cellular processes that endanger the organism. They play a key role in the regulation of both pro- and anti-inflammatory immune responses. Based on the assumption that pDC could participate in the initiation of the anti-inflammatory response to apoptotic cells, we investigated the effects of apoptotic cell-derived MMP on human pDC. The results obtained in our experiments confirmed that MMP released from apoptotic cells trigger IFN-α secretion from human pDC. They further suggest that pDC activation results from sensing of DNA contained in MMP. MMP-DNA displays a particularly strong stimulatory activity compared with MMP-RNA and other sources of DNA. Inhibition of MMP-induced IFN-α secretion by cytochalasin D, chloroquine, and an inhibitory G-rich oligodeoxynucleotide identify TLR9 as the receptor for MMP-DNA. In marked contrast to the pDC response in autoimmune patients, in healthy subjects MMP-mediated stimulation of pDC-derived IFN-α was found to be independent of FcγRIIA (CD32A). Based on our findings, we conclude that induction of pDC-derived IFN-α by MMP is a physiological event; future investigations are necessary to elucidate whether pDC activation promotes inflammation or propagates tolerance in the context of apoptotic cell clearance.