Mast cells (MCs) are potent innate immune cells that aggravate atherosclerosis through the release of proinflammatory mediators inside atherosclerotic plaques. Similarly, CD4+ T cells are... Show moreMast cells (MCs) are potent innate immune cells that aggravate atherosclerosis through the release of proinflammatory mediators inside atherosclerotic plaques. Similarly, CD4+ T cells are constituents of the adaptive immune response and accumulate within the plaques following lipid-specific activation by APCs. Recently it has been proposed that these two cell types can interact in a direct manner. However, no indication of such an interaction has been investigated in the context of atherosclerosis. In our study, we aimed to examine whether MCs can act as APCs in atherosclerosis, thereby modulating CD4+ T cell responses. We observed that MCs increased their MHC class II expression under hyperlipidemic conditions both in vivo and in vitro. Furthermore, we showed that MCs can present Ags in vivo via MHC class II molecules. Serum from high-fat diet–fed mice also enhanced the expression of the costimulatory molecule CD86 on cultured MCs, whereas OVA peptide–loaded MCs increased OT-II CD4+ T cell proliferation in vitro. The aortic CD4+ and TH1 cell content of atherosclerotic mice that lack MCs was reduced as compared with their wild-type counterparts. Importantly, we identified MCs that express HLA-DR in advanced human atheromata, indicating that these cells are capable of Ag presentation within human atherosclerotic plaques. Therefore, in this artice, we show that MCs may directly modulate adaptive immunity by acting as APCs in atherosclerosis. Show less
Cytokines of the Interleukin (IL)-12 family, consisting of IL-12, IL-23, IL-27 and IL-35, are important regulators in (chronic) inflammatory disorders such as rheumatoid arthritis and multiple... Show moreCytokines of the Interleukin (IL)-12 family, consisting of IL-12, IL-23, IL-27 and IL-35, are important regulators in (chronic) inflammatory disorders such as rheumatoid arthritis and multiple sclerosis, but also in cardiovascular diseases. Cytokines of the IL-12 family consist of two subunits and are known for their regulatory functions in the immunologic response, more specifically in the regulation and differentiation of T-helper (Th) cells such as Th1 and Th17 cells. Binding of these cytokines to its specific heterodimeric receptor results in the activation of the JAK-STAT signaling. Despite similarities in structure, the members of the IL-12 family have diverse, both pro- and anti-inflammatory, effects and functions. Because of the pro-inflammatory effects of IL-12 cytokine family members on immune responses, the IL-12 cytokines have been implicated in the development and progression of cardiovascular diseases such as atherosclerosis, but also in acute cardiovascular syndromes such as myocardial infarction and stroke. For example, patients suffering from cardiovascular disease display increased blood levels of IL-12, IL-23 and IL-27, while decreased IL-35 levels have been linked to a lower cardiovascular risk. In this review, we aim to highlight the current understandings of the IL-12 cytokine family and its specific family members to cardiovascular diseases, including both clinical and experimental studies. We will also discuss the potential of these cytokines as a biomarker in acute cardiovascular syndromes. Show less
Kritikou, E.; Duijn, J. van; Nahon, J.E.; Heijden, T. van der; Bouwman, M.; Groeneveldt, C.; ... ; Bot, I. 2018
The development of atherosclerosis is tightly regulated by the innate and adaptive immune system. Communication between these two compartments occurs, among others, upon presentation of lipid... Show moreThe development of atherosclerosis is tightly regulated by the innate and adaptive immune system. Communication between these two compartments occurs, among others, upon presentation of lipid antigens to the NKT cell population by CD1d-expressing antigen-presenting cells. Recent evidence states that also mast cells express CD1d and can directly communicate with NKT cells. However, no such relationship has been reported in atherosclerosis. Here, we aimed to elucidate in vivo the CD1d-mediated interaction between mast cells and NKT cells upon atherosclerosis progression.\n mice and subsequently placed the animals on a Western-type diet for 10 weeks.\n circulating T cells.\nThis study is the first to illustrate that disruption of the CD1d communication pathway between mast cells and NKT cells aggravates atherosclerosis, through a shift towards pro-inflammatory T cell responses. This ability of mast cell action during plaque progression sheds new light on their role in atherosclerosis. Show less
Duijn, J. van; Kritikou, E.; Benne, N.; Heijden, T. van der; Puijvelde, G.H. van; Kröner, M.J.; ... ; Slütter, B. 2018
Human endarterectomy samples analyzed by flow cytometry showed a negative correlation between the percentage of CD8+ T-cells and macrophages, suggesting a possible protective role for these cells... Show moreHuman endarterectomy samples analyzed by flow cytometry showed a negative correlation between the percentage of CD8+ T-cells and macrophages, suggesting a possible protective role for these cells in lesion development. To further test this hypothesis, LDLr-/- mice were fed a Western-type diet (WTD) for 10 weeks to induce atherosclerosis, after which they received CD8α-depleting or isotype control antibody for six weeks. Depletion of CD8+ T-cells in advanced atherosclerosis resulted in less stable lesions, with significantly reduced collagen content in the trivalve area, increased macrophage content and increased necrotic core area compared to controls. Mechanistically, we observed that CD8 depletion specifically increased the fraction of Th1 CD4+ T-cells in the lesions. Treatment of WTD-fed LDLr-/- mice with a FasL-neutralizing antibody resulted in similar changes in macrophages and CD4+ T-cell skewing as CD8+ T-cell depletion. T lymphocytes play an important role in atherosclerosis development, but the role of the CD8+ T-cell remains debated, especially in the clinically relevant advanced stages of atherosclerosis development. Here, we set out to determine the role of CD8+ T-cells in advanced atherosclerosis. These findings demonstrate for the first time a local, protective role for CD8+ T-cells in advanced atherosclerosis, through limiting accumulation of Th1 cells and macrophages, identifying a novel regulatory mechanism for these cells in atherosclerosis. Methods and Results Aims Conclusion Show less
Cardiovascular diseases are among the most frequent causes of death in the world. The main underlying pathology of cardiovascular diseases is the development of atherosclerosis in the medium and... Show moreCardiovascular diseases are among the most frequent causes of death in the world. The main underlying pathology of cardiovascular diseases is the development of atherosclerosis in the medium and large-sized arteries. The role of several immune cell subsets has been identified in atherosclerosis and it has been established that the immune system contributes to initiation and progression of cardiovascular diseases. Atherosclerosis is thus currently described as a chronic inflammatory disease and both the innate and adaptive immune cells contribute to disease initiation and progression. This suggests that targeting the ongoing inflammatory response may limit atherogenesis. This thesis discusses several therapeutic immune targets to limit atherosclerotic lesion development. The results described show the interplay between lipids and the immune system and a number of anti-inflammatory strategies to reduce atherosclerotic lesion development. The studies show a clear advantage of reducing inflammation in atherosclerotic lesion development. Future (clinical) studies identifying new targets will lead to a better-personalized therapy reducing atherosclerosis. Show less
Heijden, T. van der; Kritikou, E.; Venema, W.; Duijn, J. van; Santbrink, P.J. van; Slütter, B.; ... ; Kuiper, J. 2017
Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a... Show moreLysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development. Show less
Foks, A.C.; Puijvelde, G.H.M. van; Wolbert, J.; Kröner, M.J.; Frodermann, V.; Heijden, T. van der; ... ; Kuiper, J. 2016
AIMS Myeloid-derived suppressor cells (MDSCs) form a heterogeneous population of cells composed of early myeloid progenitor cells and immature myeloid cells, which strongly suppress pro... Show moreAIMS Myeloid-derived suppressor cells (MDSCs) form a heterogeneous population of cells composed of early myeloid progenitor cells and immature myeloid cells, which strongly suppress pro-inflammatory immune cells in inflammatory diseases. Currently, it is unknown whether MDSCs contribute to atherosclerosis, a chronic inflammatory disease in which accumulation of lipoproteins in the arterial wall activates the immune system causing abnormal vascular remodelling and vessel occlusion. Here, we investigated whether and how MDSCs contribute to the development of atherosclerosis. METHODS AND RESULTS We show that MDSCs arise in the bone marrow of LDLr(-/-) mice during atherosclerosis and strongly suppress proliferation of T cells. Adoptive transfer of MDSCs into both female and male LDLr(-/-) mice fed a Western-type diet (WTD) ameliorates atherosclerosis with 35%. We observed a 54% reduction in adventitial T cells, and more specifically, MDSCs suppress Th1 and Th17 cells. In addition, treatment with MDSCs reduces circulating pro-atherogenic B2 cells. We found two subsets of MDSCs in the bone marrow of hypercholesterolemic mice, monocytic and granulocytic MDSCs (mo- and gr-MDSCs, respectively), of which the percentage of mo-MDSCs significantly increased during WTD feeding. Moreover, mo-MDSCs completely abolished splenocyte proliferation, whereas gr-MDSCs were unable to suppress proliferation. Mechanistically, we show that MDSCs from atherosclerotic mice suppress T cells in an IFN-γ- and nitric oxide-dependent manner, which is associated with the action of mo-MDSCs. CONCLUSION This study demonstrates that MDSCs develop during atherosclerosis and reduce atherosclerosis via suppression of pro-inflammatory immune responses. Show less
Spaapen, R.M.; Blomen, V.; Veelen, P.A. van; Jongsma, M.L.; Schrikkema, B.; Heijden, T. van der; ... ; Neefjes, J. 2015
