Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

Abstract

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.

Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response

“…During the past years, blockage of IFN-α has therefore been focus of pharmacological research (Petri et al, 2013). Only recently, our group was able to prove a direct link between the release of AdMPs and IFN-α secretion, showing that AdMPs can trigger the secretion of IFN-α from plasmacytoid dendritic cells (Schiller et al, 2012). These data provide a further link between AdMPs and characteristic features of SLE.…”

“…In this context, it has been shown that autoantigens accumulate within AdMPs after induction of apoptosis (Schiller et al, 2008). Furthermore, AdMPs have been shown to modulate the function of plasmacytoid dendritic cells (the main producers of IFN-α) as well as myeloid dendritic cells (Fehr et al, 2013;Schiller et al, 2012).…”

Molecular Biology of Atherosclerosis

“…However, stimulation of pDC may have different outcomes. Thus activation of pDCs through TLR9 is reported to be a normal, physiological response to DNA released in membrane microparticles from apoptotic cells (1553). CpG ODNs able to activate Th1 responses in some settings may also promote immune tolerance through Treg with enhanced IL-10 production in other contexts (541,2122).…”

Cell-free Tumor Microparticle Vaccines Stimulate Dendritic Cells via cGAS/STING Signaling

“…5B). In addition to protein components, T-MPs also contain RNAs (21,22) that are capable of stimulating DCs through the IFN pathway (23). To determine this possibility, we knocked down RIG-I, a key sensor for RNAmediated type I IFN production, using specific siRNA during the incubation of DCs with T-MPs.…”