Oxidized Low-Density Lipoprotein Promotes Mature Dendritic Cell Transition from Differentiating Monocyte

Perrin-Cocon, Laure; Coutant, Frédéric; Agaugué, Sophie; Deforges, Séverine; André, Patrice; Lotteau, Vincent

doi:10.4049/jimmunol.167.7.3785

Cited by 126 publications

(121 citation statements)

References 50 publications

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“…Additionally, the continued high expression of MHC class II and costimulatory CD86 molecules on DCs, but not on microglia and macrophages, suggests that these DCs may remain capable of presenting myelin Ag, even if devoid of IFN-γ signaling. Interestingly, it has been shown that oxidized lipids induce a mature phenotypic signature in DCs with up-regulation of CD86, whereas at the same time phagocytic activity is inhibited (60). Similarly, oxidized lipids have been shown to promote the differentiation of a macrophage cell line into a DC phenotype in vitro (61), as is consistent with our data showing an increase in the number of DCs in IFN-γR −/− mice and WT mice treated with anti-IFN-γ mAb.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ −/− ) or IFN-γ receptor knockout (IFN-γR −/− ) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, "free" myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-L-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ-signalingdeficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.

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Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…We have previously shown that the presence of oxidized LDL during monocyte differentiation to DC yielded phenotypically and functionally mature DC (11). Optimal reactivity of monocytes was obtained when oxLDL was added during late stages of differentiation in GM-CSF and IL-4.…”

Section: Cd86 Expression Induced By Lipophilic Molecules Of Oxldlmentioning

confidence: 99%

Mature Dendritic Cell Generation Promoted by Lysophosphatidylcholine

Coutant

Perrin-Cocon

Agaugué

et al. 2002

The Journal of Immunology

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During the acute phase response the interplay between high density lipoproteins and low density lipoproteins (LDL) favors transient generation of oxidized LDL with proinflammatory activities. We hypothesized that oxidative modification of LDL is an endogenous signal for the immune system and have shown that oxidized LDL promotes mature dendritic cell transition from monocyte therefore linking the non specific acute phase response to adaptive immunity. Lysophosphatidylcholine (LPC) is a major lipid component of oxidized LDL with reported proinflammatory activities. We now report that LPC acts through G protein-coupled receptors on differentiating monocytes to generate mature dendritic cells with the ability to stimulate IL-2 and IFNγ production by allogeneic T lymphocytes. LPC is most effective in lipoprotein deprived serum and can be inhibited by an excess of native LDL reflecting normal plasma conditions. Therefore, by controlling the balance between native and oxidized lipoproteins and the resulting production of LPC, the acute phase reactants may provide a context of antigen presentation which is transiently favorable to immune activation. Intralipid, a therapeutic lipid emulsion for parenteral nutrition with unexplained immunomodulatory properties, also blocked LPC activity. This opens perspectives for the understanding and treatment of acute and chronic inflammatory diseases.

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“…It is accompanied by alterations in lipoprotein composition that result in generation of oxidized low density lipoprotein (oxLDL) and oxidized phospholipids [3,4]. OxLDL were first studied for their role in chronic inflammation during atherosclerosis [5] but recent work indicates that infection and inflammation also result in increased levels of oxLDL [6] and modified lipids that can be detected by the immune system [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Sensing the danger is a crucial function of Ag-presenting cells, that is necessary to initiate primary immune responses [35,36]. We previously hypothesized that oxLDL and modified phospholipids such as LPC generated during APR could signal the presence of a dangerous situation to the immune system and showed that oxLDL and LPC could favour the development of adaptive immunity by promoting mature DC generation in vitro [7][8][9]. It is shown here that LPC can prime both cellular and humoral Ag-specific responses, confirming that the APR regulates the production of critical immunoregulatory molecules by controlling the biochemical composition of lipoproteins.…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine is a natural adjuvant that initiates cellular immune responses

Perrin-Cocon

Agaugué

Coutant

et al. 2006

Vaccine

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The discovery of new adjuvants that can stimulate the immune response to protein antigens is a major issue for the development of subunit vaccines. Lipoprotein oxidation occurring during the acute phase response (APR) to aggression of the organism, provide signals of danger that are detected by dendritic cells (DC). Among other instructive molecules generated during the APR, lysophosphatidylcholine (LPC) promotes mature DC generation from differentiating human monocytes in vitro. It is shown here that LPC also controls the initiation of an adaptive immune response in vivo. LPC displays adjuvant properties when injected to mice in mixture with various antigens. Immunizations with LPC induced the production of antigen-specific antibodies with an efficiency similar to Alum, the reference adjuvant for human vaccination.Importantly, LPC also induced cytotoxic T cell responses, opening perspectives for vaccine development. Therefore, LPC is a natural adjuvant for the immune system, inducing humoral and cellular immune responses.

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Oxidized Low-Density Lipoprotein Promotes Mature Dendritic Cell Transition from Differentiating Monocyte

Cited by 126 publications

References 50 publications

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Mature Dendritic Cell Generation Promoted by Lysophosphatidylcholine

Lysophosphatidylcholine is a natural adjuvant that initiates cellular immune responses

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