Abstract
Dendritic cells (DCs) can be sub-divided into various subsets that play specialized roles in priming of adaptive immune responses. Atherosclerosis is regarded as a chronic inflammatory disease of the vessel wall and DCs can be found in non-inflamed and diseased arteries. We here performed a systematic analyses of DCs subsets during atherogenesis. Our data indicate that distinct DC subsets can be localized in the vessel wall. In C57BL/6 and low density lipoprotein receptor-deficient (Ldlr −/−) mice, CD11c+ MHCII+ DCs could be discriminated into CD103− CD11b+F4/80+, CD11b+F4/80− and CD11b−F4/80− DCs and CD103+ CD11b−F4/80− DCs. Except for CD103− CD11b− F4/80− DCs, these subsets expanded in high fat diet-fed Ldlr −/− mice. Signal-regulatory protein (Sirp)-α was detected on aortic macrophages, CD11b+ DCs, and partially on CD103− CD11b− F4/80− but not on CD103+ DCs. Notably, in FMS-like tyrosine kinase 3-ligand-deficient (Flt3l −/−) mice, a specific loss of CD103+ DCs but also CD103− CD11b+ F4/80− DCs was evidenced. Aortic CD103+ and CD11b+ F4/80− CD103− DCs may thus belong to conventional rather than monocyte-derived DCs, given their dependence on Flt3L-signalling. CD64, postulated to distinguish macrophages from DCs, could not be detected on DC subsets under physiological conditions, but appeared in a fraction of CD103− CD11b+ F4/80− and CD11b+ F4/80+ cells in atherosclerotic Ldlr −/− mice. The emergence of CD64 expression in atherosclerosis may indicate that CD11b+ F4/80− DCs similar to CD11b+ F4/80+ DCs are at least in part derived from immigrated monocytes during atherosclerotic lesion formation. Our data advance our knowledge about the presence of distinct DC subsets and their accumulation characteristics in atherosclerosis, and may help to assist in future studies aiming at specific DC-based therapeutic strategies for the treatment of chronic vascular inflammation.
Highlights
Atherosclerosis is regarded as a chronic inflammatory disease of the vessel wall [1]
The CD1032 fraction of aortic dendritic cells (DCs) could further be subdivided into a large population of CD11c+ CD11b+ F4/80+ DCs and a less abundant CD11c+ CD11b+ F4/802 subset, as described previously [10], and CD11c+ CD11b2 F4/802 cells (Figure 2)
After segregation of CD11c2 MHCII+ cells, denominated as macrophages [10,12,13], we further discriminated CD11c+ MHCII+ ‘DCs’ into a distinct CD103+ population, and CD1032 DCs that could further be subdivided into CD11b2 F4/80+ and CD11b+ F4/80+ DCs, similar to DC populations defined by gating strategies proposed by others [6,10]
Summary
Atherosclerosis is regarded as a chronic inflammatory disease of the vessel wall [1]. A systematic analysis of the presence of these subsets and their accumulation in the course of lesion development, has not yet been performed It remains to be determined if these cell subsets denominated as DCs and macrophages represent true lineage subsets with distinct transcriptional profiles, we here have adopted and refined the gating strategy applied by Choi et al and others and used the term DCs when describing cells that express CD11c, and macrophages for CD11c2 cells [6,10,12,13]; we have characterized and quantified these cell subsets in C57BL/6 mice and atherosclerosis-prone mice fed a high fat diet. We applied novel surface markers to characterize these cell subsets during atherogenesis
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