The glucocorticoid dexamethasone programs human dendritic cells for enhanced phagocytosis of apoptotic neutrophils and inflammatory response

Hodrea, Judit; Májai, Gyöngyike; Doró, Zoltán; Zahuczky, Gábor; Pap, Attila; Rajnavölgyi, Éva; Fésüs, László

doi:10.1189/jlb.0511243

Cited by 26 publications

(22 citation statements)

References 61 publications

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“…We chose DCs as a source of dying material to avoid contaminating mRNA from other cellular sources, as many cells constitutively express IL-12p35 to varying degrees. In addition, the ratio (1:5) of viable:dying cells that we used is in line with ratios used in other studies [27,30,31,53]. We first observed that uptake of apoptotic or necrotic material by DCs altered their allostimulatory capacity, with apoptotic cell uptake decreasing T cell proliferation and IFN-␥ production, whereas necrotic cell uptake increased proliferation and IFN-␥ production.…”

Section: Discussionsupporting

confidence: 76%

“…Rather than merely being passively noninflammatory, these studies imply that apoptotic cells can actively infer an immunoregulatory state within the ingesting DCs [29,30]. Much of this work has focused on immunogenic DCs, and there have been few studies looking at the phagocytic potential of TolDCs and the subsequent functional consequences for these cells [31].…”

Section: Introductionmentioning

confidence: 99%

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Phagocytosis of apoptotic or necrotic cells differentially regulates the transcriptional expression of IL-12 family members in dendritic cells

Dixon

O'flynn

Kooij

et al. 2014

Journal of Leukocyte Biology

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Uptake of apoptotic cells by DCs is considered to contribute to induction and maintenance of immunological tolerance. TolDCs are sought after as cellular therapy in transplantation and autoimmunity and can be generated in vitro using GCs. In this study, we investigated how uptake of dead cells affects the production and expression of different members of the IL-12 family by immature DCs or TolDCs. We show that compared to regular immature DCs, TolDCs display elevated levels of PS-recognizing bridge molecule receptors αvβ5 and CD36, and have enhanced phagocytic abilities with accelerated uptake of apoptotic cells. We confirm that apoptotic cell uptake results in diminished production of IL-12p40 and IL-12p70 by DCs. We now show that this also results in increased expression of IL-12p35 and Ebi3. TolDCs completely lack expression of IL-12p40 yet have enhanced levels of Ebi3 and IL-12p35. Uptake by TolDCs of apoptotic or necrotic cells does not affect the expression of Ebi3/IL-12p35 and also does not increase IL-12p40. This is distinct from the culture of immature DCs with necrotic cells, which is sufficient to induce IL-12p40 secretion. Conversely, ingestion of apoptotic cells by DCs leads to increased expression of IL-12p35 and Ebi3 without affecting IL-12p40. In conclusion, we have shown that uptake of apoptotic versus necrotic cells by DCs differentially regulates members of the IL-12 family. Apoptotic cells favor expression of Ebi3 and IL-12p35, and we propose that differential regulation of the IL-12 family is an additional mechanism in determining the immune response to dying cells.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Phagocytosis of apoptotic or necrotic cells differentially regulates the transcriptional expression of IL-12 family members in dendritic cells

Dixon

O'flynn

Kooij

et al. 2014

Journal of Leukocyte Biology

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“…TAM receptors have also been described as pleiotropic-negative regulators of TLRs and cytokine receptor signaling in murine DCs [11]. It has been described how steroids regulate expression of MERTK and PROS1 and enhance their activity in AC clearance in human macrophages [25], as well as in DCs [26]. Although the importance of MERTK in the engulfment and efficient clearance of AC in humans has been investigated, little is known about the immunomodulatory role of MERTK in humans, as it may differ from animal models.…”

Section: Discussionmentioning

confidence: 99%

MERTK as negative regulator of human T cell activation

Cabezón

Silva

Flórez‐Grau

et al. 2015

Journal of Leukocyte Biology

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The aim of this study was to test the hypothesis whether MERTK, which is up-regulated in human DCs treated with immunosuppressive agents, is directly involved in modulating T cell activation. MERTK is a member of the TAM family and contributes to regulating innate immune response to ACs by inhibiting DC activation in animal models. However, whether MERTK interacts directly with T cells has not been addressed. Here, we show that MERTK is highly expressed on dex-induced human tol-DCs and participates in their tolerogenic effect. Neutralization of MERTK in allogenic MLR, as well as autologous DC-T cell cultures, leads to increased T cell proliferation and IFN-γ production. Additionally, we identify a previously unrecognized noncell-autonomous regulatory function of MERTK expressed on DCs. Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK ligand PROS1. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine proproliferative mechanism. Collectively, these results suggest that MERTK on DCs controls T cell activation and expansion through the competition for PROS1 interaction with MERTK in the T cells. In conclusion, this report identified MERTK as a potent suppressor of T cell response.

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“…[4][5][6] Strategies could focus on the phagocyte and aim to stimulate the molecular machinery executing phagocytosis 23 or focus on the phagocytic prey and label it with additional 'eat me' signals. 24 Here we present the strategy to add additional 'eat me' signals to the apoptotic cell by targeting PS, which is a ubiquitous hallmark of apoptosis independent of cell type and cell death-inducing trigger.…”

Section: Discussionmentioning

confidence: 99%

Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells

et al. 2012

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Impaired efferocytosis has been shown to be associated with, and even to contribute to progression of, chronic inflammatory diseases such as atherosclerosis. Enhancing efferocytosis has been proposed as strategy to treat diseases involving inflammation. Here we present the strategy to increase 'eat me' signals on the surface of apoptotic cells by targeting cell surfaceexpressed phosphatidylserine (PS) with a variant of annexin A5 (Arg-Gly-Asp-annexin A5, RGD-anxA5) that has gained the function to interact with a v b 3 receptors of the phagocyte. We describe design and characterization of RGD-anxA5 and show that introduction of RGD transforms anxA5 from an inhibitor into a stimulator of efferocytosis. RGD-anxA5 enhances engulfment of apoptotic cells by phorbol-12-myristate-13-acetate-stimulated THP-1 (human acute monocytic leukemia cell line) cells in vitro and resident peritoneal mouse macrophages in vivo. In addition, RGD-anxA5 augments secretion of interleukin-10 during efferocytosis in vivo, thereby possibly adding to an anti-inflammatory environment. We conclude that targeting cell surfaceexpressed PS is an attractive strategy for treatment of inflammatory diseases and that the rationally designed RGD-anxA5 is a promising therapeutic agent.

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The glucocorticoid dexamethasone programs human dendritic cells for enhanced phagocytosis of apoptotic neutrophils and inflammatory response

Abstract: Differentiation of DC with dexamethasone leads to elevated apoptotic neutrophil phagocytosis, through the up‐regulation of apoptophagocytic genes, and to proinflammatory T cell response.

Cited by 26 publications

References 61 publications

Phagocytosis of apoptotic or necrotic cells differentially regulates the transcriptional expression of IL-12 family members in dendritic cells

Phagocytosis of apoptotic or necrotic cells differentially regulates the transcriptional expression of IL-12 family members in dendritic cells

MERTK as negative regulator of human T cell activation

Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells

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