Ablation of CD8α+ dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice

Legein, Bart; Janssen, Edith M.; Theelen, Thomas; Gijbels, Marion J.J.; Walraven, Joep; Klarquist, Jared; Hennies, Cassandra M.; Wouters, Kristiaan; Seijkens, Tom; Wijnands, Erwin; Sluimer, Judith C.; Lutgens, Esther; Zenke, Martin; Hildner, Kai; Biessen, Erik A. L.; Temmerman, Lieve

doi:10.1038/srep15414

Cited by 20 publications

(36 citation statements)

References 58 publications

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“…The expansion of CD11c + APCs has previously been linked to an atheroprotective decrease in plasma cholesterol levels [ 7 ]. We did not observe any differences in serum lipids between Ldlr -/- Batf3 -/- and Ldlr -/- mice fed a high fat diet, implying that Batf3-dependent cells are not involved in cholesterol metabolism, in line with findings in chimeric Ldlr -/- mice reconstituted with Batf3 -/- bone marrow [ 12 ], Flt3 -/- Ldlr -/- mice that lack CD103 + DCs in the aorta [ 14 ] and in an ApoE -/- Batf3 -/- mouse model [ 13 ].…”

Section: Discussionsupporting

confidence: 83%

“…The role of Batf3-dependent APCs in the development of atherosclerosis is not clear. In a study in which lethally-irradiated low density lipoprotein receptor-deficient ( Ldlr -/- ) mice were reconstituted with bone marrow (BM) from Batf3 -/- mice and as a consequence lacked CD8α + DCs, no differences in plaque development were observed [ 12 ]. More recently, a study using Apolipoprotein E-deficient ( ApoE -/- ) Batf3 -/- mice has proposed that Batf3-dependent DCs promote atherosclerosis through induction of Th1 responses in the aorta [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice

et al. 2017

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Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α+ and CD103+ DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr-/-)-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α+ and CD103+ antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice

et al. 2017

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“…Moreover, in contrast to those results, atherosclerotic plaque formation and stability were not altered in chimeric Ldlr −/− mice transplanted with bone marrow from Batf3(basic leucine zipper transcription factor ATF-like 3)-deficient mice that lack the CD8α + DC subset, compared with Ldlr −/− mice transplanted with a control bone marrow. 29 Our study differs from the previous ones in that we report on the deletion of a specific pattern recognition receptor selectively expressed by CD8α + DCs, while preserving the other functions of this DC subset. Our present results clearly indicate that the specific deletion of DNGR-1 in CD8α + DCs promotes atherosclerosis, identifying a previously unrecognized proatherogenic function of CD8α + DCs in the development of atherosclerosis.…”

Section: Haddad Et Al Dngr-1 Il-10 and Atherosclerosis 241contrasting

confidence: 79%

The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice

Haddad

Lahoute

Clément

et al. 2017

Circulation Research

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Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α + subset of dendritic cells (CD8α + DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. Objective: We sought to address the impact of total, bone marrow–restricted, or CD8α + DC–restricted deletion of DNGR-1 on atherosclerosis development. Methods and Results: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)–deficient mice ( Apoe −/− ) and bone marrow–restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)–deficient mice ( Ldlr −/− ) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow–derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α + DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. Conclusions: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation.

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“…Another recent study used Batf3 −/− chimeras, in which lethally irradiated Ldlr −/− mice were reconstituted with bone marrow from Batf3 −/− mice. This study showed that loss of CD8α + DCs in hyperlipidemic mice profoundly reduced cross-priming ability, nevertheless it did not influence lesion development (Legein et al, 2015). Different from the previous study, we used another strategy to prepare Batf3 −/− Apoe −/− mice through hybridization of Apoe −/− mice and Batf3 −/− mice.…”

Section: Discussionmentioning

confidence: 90%

Batf3-dependent CD8α + Dendritic Cells Aggravates Atherosclerosis via Th1 Cell Induction and Enhanced CCL5 Expression in Plaque Macrophages

Liu

Duan

et al. 2017

EBioMedicine

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Dendritic cells (DCs) play an important role in controlling T cell-mediated adaptive immunity in atherogenesis. However, the role of the basic leucine zipper transcription factor, ATF-like 3 (Batf3)-dependent CD8α+ DC subset in atherogenesis remains unclear. Here we show that Batf3−/− Apoe−/− mice, lacking CD8α+ DCs, exhibited a significant reduction in atherogenesis and T help 1 (Th1) cells compared with Apoe−/− controls. Then, we found that CD8α+ DCs preferentially induce Th1 cells via secreting interleukin-12 (IL-12), and that the expression of interferon-gamma (IFN-γ)or chemokine (C-C motif) ligand 5 (CCL5) in aorta were significantly decreased in Batf3−/− Apoe−/− mice. We further demonstrated that macrophages were the major CCL5-expressing cells in the plaque, which was significantly reduced in Batf3−/− Apoe−/− mice. Furthermore, we found CCL5 expression in macrophages was promoted by IFN-γ. Finally, we showed that Batf3−/− Apoe−/− mice displayed decreased infiltration of leukocytes in the plaque. Thus, CD8α+ DCs aggravated atherosclerosis, likely by inducing Th1 cell response, which promoted CCL5 expression in macrophages and increased infiltration of leukocytes and lesion inflammation.

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Ablation of CD8α+ dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice

Cited by 20 publications

References 58 publications

Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice

Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice

The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice

Batf3-dependent CD8α + Dendritic Cells Aggravates Atherosclerosis via Th1 Cell Induction and Enhanced CCL5 Expression in Plaque Macrophages

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