Apoptotic-cell-derived membrane vesicles induce an alternative maturation of human dendritic cells which is disturbed in SLE

Fehr, Eva-Marie; Spoerl, Silvia; Heyder, Petra; Herrmann, Martin; Bekeredjian‐Ding, Isabelle; Blank, Norbert; Lorenz, Hanns‐Martin; Schiller, Martin

doi:10.1016/j.jaut.2012.08.003

Cited by 28 publications

(28 citation statements)

References 46 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…Both secondary and primary necrotic cells release their content into the extracellular space and subsequently induce an inflammatory reaction. Different responses of antigenpresenting cells to AdMPs, whole apoptotic cells and necrotic cells have been described (Fehr et al, 2013). We were interested whether the observed effect of IFN-α on phagocytosis of AdMPs was also present if whole apoptotic or necrotic cells were engulfed, or whether this effect was specific for AdMPs.…”

Section: Phagocytosis Of Admps By Monocytes Shows a Dose-dependent Inmentioning

confidence: 99%

“…Comparing cells obtained from SLE patients to cells obtained from healthy donors, we did not observe any difference in the amount of engulfed AdMPs (data not shown). AdMPs containing autoantigens as well as potential neo-epitopes are effectively cleared by professional phagocytes and antigenpresenting cells (Fehr et al, 2013;Schiller et al, 2008). Whole apoptotic cells, however, can lose their membrane integrity during later stages of apoptotic cell death and enter a post-apoptotic stage, called secondary necrosis.…”

Section: Phagocytosis Of Admps By Monocytes Shows a Dose-dependent Inmentioning

confidence: 99%

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

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Heyder

Krienke

et al. 2015

Journal of Cell Science

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A dysregulation in the clearance of apoptotic material is considered a major pathogenetic factor for the emergence of autoimmune diseases. Apoptotic-cell-derived membrane microparticles (AdMPs), which are released from the cell surface during apoptosis, have been implicated in the pathogenesis of autoimmunity. Also of importance are cytokines, such as interferon-α (IFN-α), which is known to be a major player in patients with systemic lupus erythematosus (SLE). This study investigates the combined effect of AdMPs and IFN-α on professional phagocytes. In the presence of IFN-α, phagocytosis of AdMPs by human monocytes was significantly increased in a dosedependent manner. The combination of AdMPs and raised IFN-α concentrations resulted in an increase in the secretion of proinflammatory cytokines and an upregulation of surface molecule expression involved in antigen uptake. In addition, macrophage polarisation was shifted towards a more inflammatory type of cell. The synergism between IFN-α and AdMPs seemed to be mediated by an upregulation of phosphorylated STAT1. Our results indicate that IFN-α, together with AdMPs, amplify the initiation and maintenance of inflammation. This mechanism might especially play a crucial role in disorders with a defective clearance of apoptotic material.

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Section: Discussionmentioning

confidence: 99%

Section: Phagocytosis Of Admps By Monocytes Shows a Dose-dependent Inmentioning

confidence: 99%

Section: Phagocytosis Of Admps By Monocytes Shows a Dose-dependent Inmentioning

confidence: 99%

See 1 more Smart Citation

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

Nießen

Heyder

Krienke

et al. 2015

Journal of Cell Science

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“…Whole lymphocyte fractions were treated with UV‐B radiation (1·8–2·5 mW/cm 2 for 1·5 hr) to induce apoptosis, which was confirmed by flow cytometry using AnnexinV and propidium iodide staining (BD Bioscience). Apoptotic cells (ApoCells) were collected by centrifugation for 10 min (500 g ), and DNA concentration was determined by silica‐based DNA purification (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

et al. 2017

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Systemic lupus erythematosus (SLE) is an autoimmune disease with unrestrained T-cell and B-cell activity towards self-antigens. Evidence shows that apoptotic cells (ApoCells) trigger an autoreactive response against nuclear antigens in susceptible individuals. In this study, we focus on generating and characterizing tolerogenic dendritic cells (tolDCs) to restore tolerance to ApoCells. Monocyte-derived dendritic cells (DCs) from healthy controls and patients with SLE were treated with dexamethasone and rosiglitazone to induce tolDCs. Autologous apoptotic lymphocytes generated by UV irradiation were given to tolDCs as a source of self-antigens. Lipopolysaccharide (LPS) was used as a maturation stimulus to induce the expression of co-stimulatory molecules and secretion of cytokines. TolDCs generated from patients with SLE showed a reduced expression of co-stimulatory molecules after LPS stimulation compared with mature DCs. The same phenomenon was observed in tolDCs treated with ApoCells and LPS. In addition, ApoCell-loaded tolDCs stimulated with LPS secreted lower levels of interleukin-6 (IL-6) and IL-12p70 than mature DCs without differences in IL-10 secretion. The functionality of tolDCs was assessed by their capacity to prime allogeneic T cells. TolDCs displayed suppressor properties as demonstrated by a significantly reduced capacity to induce allogeneic T-cell proliferation and activation. ApoCell-loaded tolDCs generated from SLE monocytes have a stable immature/tolerogenic phenotype that can modulate CD4 T-cell activation. These properties make them suitable for an antigen-specific immunotherapy for SLE.

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“…Interestingly, Fehr et al . have recently demonstrated a different modulating effect of apoptotic MVs, which were ex vivo -generated from human lymphocytes, on DC from healthy individuals and SLE patients [41]. …”

Section: Discussionmentioning

confidence: 99%

Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice

et al. 2015

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IntroductionSystemic lupus erythematosus is associated with a persistent circulation of modified autoantigen-containing apoptotic debris that might be capable of breaking tolerance. We aimed to evaluate apoptotic microvesicles obtained from lupus or control mice for the presence of apoptosis-associated chromatin modifications and for their capacity to stimulate dendritic cells (DC) from lupus and control mice.MethodApoptotic microvesicles were in vitro generated from splenocytes, and ex vivo isolated from plasma of both MRL/lpr lupus mice and normal BALB/c mice. Microvesicles were analyzed using flow cytometry. Bone marrow-derived (BM)-DC cultured from MRL/lpr or BALB/c mice were incubated with microvesicles and CD40 expression and cytokine production were determined as measure of activation.ResultsMicrovesicles derived from apoptotic splenocytes or plasma of MRL/lpr mice contained more modified chromatin compared to microvesicles of BALB/c mice, and showed enhanced activation of DC, either from MRL/lpr or BALB/c mice, and consecutively an enhanced DC-mediated activation of splenocytes. The content of apoptosis-modified chromatin in microvesicles of apoptotic splenocytes correlated with their potency to induce interleukin-6 (IL-6) production by DC. Microvesicle-activated MRL/lpr DC showed a significant higher production of IL-6 and tumor growth factor-β (TGF-β) compared to BALB/c DC, and were more potent in the activation of splenocytes.ConclusionApoptotic microvesicles from MRL/lpr mice are more potent activators of DC, and DC from MRL/lpr mice appear relatively more sensitive to activation by apoptotic microvesicles. Our findings indicate that aberrations at the level of apoptotic microvesicles and possibly DC contribute to the autoimmune response against chromatin in MRL/lpr mice.

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Apoptotic-cell-derived membrane vesicles induce an alternative maturation of human dendritic cells which is disturbed in SLE

Cited by 28 publications

References 46 publications

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

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

Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype

Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice

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