Induction of type I IFN is a physiological immune reaction to apoptotic cell-derived membrane microparticles.
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.
Division of Rheumatology, Department of Internal Medicine V, University Hospital Heidelberg, D-69120 Heidelberg, Germany. martin.schiller@med.uni-heidelberg.de
Martin
M
Schiller
Marijo
M
Parcina
Petra
P
Heyder
Sandra
S
Foermer
Jenny
J
Ostrop
Albrecht
A
Leo
Klaus
K
Heeg
Martin
M
Herrmann
Hanns-Martin
HM
Lorenz
Isabelle
I
Bekeredjian-Ding
D017209:Apoptosis / Q000276:immunology*; D002469:Cell Separation; D055252:Cell-Derived Microparticles / Q000276:immunology*; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007370:Interferon Type I; D004247:DNA