Abstract
Background and AimsPlasmacytoid dendritic cells (pDCs) are a small subset of dendritic cells and the main producers of type I interferons. Besides their contribution to tolerance, they are known to be involved in autoimmune diseases and have recently been implicated in atherosclerosis. However, their precise involvement, particularly in advanced lesion development, remains elusive. Hence, we investigated the role of pDCs in atherogenesis vs atheroprogression by specifically depleting this cell population using the BDCA2-DTR mouse model bred to Apolipoprotein E (Apoe -/-) deficient mice.Methods and ResultsOur results revealed that continuous diphtheria toxin-induced pDC depletion in Apoe -/- BDCA2-DTR mice receiving a high-fat diet (HFD) for 4 weeks did not alter lesion size or composition. Instead, these mice displayed increased B cell numbers and altered levels of inflammatory cytokines. Analysis of depletion efficiency showed that complete pDC depletion could only be sustained for one week and reoccurring pDCs sorted after 4 weeks did not express DTR anymore. Consequently, we analyzed lesion development in a model of partial carotid ligation, inducing established lesions after 5 weeks of HFD feeding, and only depleted pDCs during the last week of 5 weeks HFD feeding. Despite short-term, but efficient pDC depletion, we observed no differences in atherosclerotic lesion development, but changes in inflammatory cytokine titers. To assure the functionality of the BDCA2-DTR model in acute settings, we additionally examined the effect of pDC depletion in an indirect acute lung injury (iALI) model. This time, efficient pDC depletion resulted in a significantly reduced macrophage and neutrophil accumulation in the lung 12 hours after LPS challenge, underlining a pro-inflammatory role of pDCs in the innate immune response in iALI.ConclusionTaken together, the BDCA2-DTR mouse model only allows efficient pDC depletion for one week, which subsequently restricts its usability to more acute but not chronic inflammatory disease models.
Highlights
Plasmacytoid dendritic cells are a scarce subset of bone marrow-derived dendritic cells (DCs), known to produce large amounts of type I interferons (IFN-I) in response to mainly viral pathogens
Our results revealed that continuous diphtheria toxin-induced Plasmacytoid dendritic cells (pDCs) depletion in Apoe-/BDCA2-DTR mice receiving a high-fat diet (HFD) for 4 weeks did not alter lesion size or composition
Analysis of depletion efficiency showed that complete pDC depletion could only be sustained for one week and reoccurring pDCs sorted after 4 weeks did not express DTR anymore
Summary
Plasmacytoid dendritic cells (pDCs) are a scarce subset of bone marrow-derived dendritic cells (DCs), known to produce large amounts of type I interferons (IFN-I) in response to mainly viral pathogens. PDCs are involved in a variety of other functions including the support of T cell survival, B cell differentiation [2], conventional DC (cDC) activation, and T cell-mediated immune responses during chronic infection [3] They exert tolerogenic functions e.g. via indoleamine-pyrrole 2,3-dioxygenase or granzyme B[4], and play an important role in the pathophysiology of different autoimmune diseases like psoriasis and systemic lupus erythematosus (SLE)[5]. Plasmacytoid dendritic cells (pDCs) are a small subset of dendritic cells and the main producers of type I interferons Besides their contribution to tolerance, they are known to be involved in autoimmune diseases and have recently been implicated in atherosclerosis. We investigated the role of pDCs in atherogenesis vs atheroprogression by depleting this cell population using the BDCA2-DTR mouse model bred to Apolipoprotein E (Apoe-/-) deficient mice
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