Dendritic Cells in Cardiovascular Diseases

Abstract

HomeCirculationVol. 128, No. 24Dendritic Cells in Cardiovascular Diseases Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBDendritic Cells in Cardiovascular DiseasesEpiphenomenon, Contributor, or Therapeutic Opportunity Anette Christ, PhD, Lieve Temmerman, PhD, Bart Legein, MSc, Mat J.A.P. Daemen, MD, PhD and Erik A.L. Biessen, PhD Anette ChristAnette Christ From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands (A.C., L.T., B.L., E.A.L.B.); Department of Cell Biology, Institute for Biomedical Engineering, Aachen University Hospital, Aachen, Germany (A.C.); and Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands (M.J.A.P.D.). Search for more papers by this author , Lieve TemmermanLieve Temmerman From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands (A.C., L.T., B.L., E.A.L.B.); Department of Cell Biology, Institute for Biomedical Engineering, Aachen University Hospital, Aachen, Germany (A.C.); and Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands (M.J.A.P.D.). Search for more papers by this author , Bart LegeinBart Legein From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands (A.C., L.T., B.L., E.A.L.B.); Department of Cell Biology, Institute for Biomedical Engineering, Aachen University Hospital, Aachen, Germany (A.C.); and Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands (M.J.A.P.D.). Search for more papers by this author , Mat J.A.P. DaemenMat J.A.P. Daemen From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands (A.C., L.T., B.L., E.A.L.B.); Department of Cell Biology, Institute for Biomedical Engineering, Aachen University Hospital, Aachen, Germany (A.C.); and Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands (M.J.A.P.D.). *Drs Daemen and Biessen contributed equally to this work. Search for more papers by this author and Erik A.L. BiessenErik A.L. Biessen From the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands (A.C., L.T., B.L., E.A.L.B.); Department of Cell Biology, Institute for Biomedical Engineering, Aachen University Hospital, Aachen, Germany (A.C.); and Department of Pathology, Amsterdam Medical Center, Amsterdam, The Netherlands (M.J.A.P.D.). *Drs Daemen and Biessen contributed equally to this work. Search for more papers by this author Originally published17 Dec 2013https://doi.org/10.1161/CIRCULATIONAHA.113.003364Circulation. 2013;128:2603–2613IntroductionCardiovascular diseases (CVDs) are one of the leading causes of mortality worldwide.1 It has been so for decades, notwithstanding a wide array of – mostly preventive – treatment modalities targeting known risk factors, such as hyperlipidemia, type 2 diabetes mellitus, hypertension, or obesity. Recent technical and conceptual advances have unveiled important contributions of the immune system in the pathophysiology of a variety of CVDs such as atherosclerosis, ischemic stroke, chronic heart failure, and other myocardial conditions like myocardial ischemia and reperfusion, viral myocarditis, and cardiac transplantation.2–4 In many of these disorders, so-called danger-associated molecular patterns (DAMPs), released from necrotic tissue and dying cells, can lead to the activation of certain immune cell populations such as monocytes/ macrophages, granulocytes, and T cells, thus aggravating ongoing inflammatory processes at the lesion site. Dendritic cells (DCs) are key modulators of immunity, pivotal in directing innate and adaptive immune responses against microbial, viral, but also modified self-antigens present at the sites of injury. Given the tissue trauma underlying various CVDs, it is not surprising that recent observations have allocated a regulatory role for DCs in CVD-associated immune responses. Interestingly, nondiseased arteries of young individuals were seen to host a network of resident vascular DCs (CD1a+ S100+ lag+ CD31− CD83− CD86−),5 representing a phenotype related to Langerhans cells in the skin. In agreement, monocyte-derived CD11c+ CD68+ dendritic cells could be detected in the atherosclerosis-prone lesser curvature and aortic sinus in inbred atherosclerosis-susceptible (C57Bl/6), but not resistant mouse strains (balb/c).6 Murine vascular resident DCs express an immature phenotype with low expression of costimulatory molecules, and are present in the subendothelial space with occasional probing into the vascular lumen.DCs have also been observed in human heart and in cardiac valves of healthy C57BL/6 mice.7 It is assumed that these immature, resident DCs contribute to the maintenance of vascular homeostasis and tolerance by scanning their microenvironment for self- and non–self-antigens. Indeed, Choi and coworkers8 were able to show that resident DCs, isolated from the aorta and the valves of wild-type mice, have the capacity to present antigens to CD8+ T cells in vitro and in vivo, indicating that they are fully functional in eliciting a T-cell response. In diseased vessels, the heart and brain of human CVD patients, but also in the circulation, DC subset numbers were reported to be modified, associating DCs with CVD onset and progression.9–11 This notion is substantiated by a wealth of experimental animal studies addressing the involvement of DCs in CVD. However, it remains mainly unsettled whether the actions of different DC subsets are either detrimental or beneficial for lesion formation. Then again, DC function may depend on lesion stage. This review thus aims to provide an in-depth overview of the role of DC subsets in several cardiovascular conditions in human and experimental animal models to reveal underlying patterns, expose pitfalls and shortcomings in our current understanding of the function of DCs in CVD, and define open/unresolved questions required to enable a thorough appreciation of the validity and potential of DCs as therapeutic target in CVD.Dendritic Cells: Conductors of Innate and Adaptive Immune ResponsesDCs are professional antigen-presenting cells (APCs) that originate from hematopoietic precursors in the bone marrow and are distributed throughout the whole body. DCs have the unique ability to induce T-cell responses by capturing, processing, and presenting antigens to naïve T cells. As such, they are the central mediators of adaptive immune responses.12 Since the discovery by Steinmann and Cohn,13 DCs were seen to represent a heterogeneous family of cells, differing in terms of development, migratory cues, compartmentalization, phenotype, and immunologic functions. So far, they are categorized into 4 main subsets: conventional DCs (cDCs), plasmacytoid DCs (pDCs), Langerhans cells, and monocyte-derived inflammatory DCs, characterized by the expression of a panel of specific surface markers.14 For further details we refer the reader to the online-only Data Supplement Appendix.Blood Circulating DC Subsets in Patients With Coronary and Peripheral Arterial DiseaseAs an indirect measure of DCs' association with CVD, DC numbers and functionality have been evaluated in the blood of patients with CVD, such as coronary and peripheral artery disease.15 In 2006, van Vre and coworkers were the first to describe a marked decrease in circulating DCs (circulating cDCs and pDCs) in patients with coronary artery disease (CAD), defined by angiography as >50% stenosis in ≥1coronary arteries.16 Until now, several studies confirmed a significant decrease in blood DCs (cDCs and pDCs) in CAD patients, irrespective of CAD grade (stable versus unstable angina pectoris, acute myocardial infarction), number of diseased vessels, or subset markers used for DC enumeration.15,17–23 In sharp contrast, Shi and colleagues24 reported increased circulating cDCs and unaltered pDC numbers in patients with stable CAD. By investigating the distribution of circulating DCs in patients with different stages of peripheral arterial disease, including patients with intermittent claudication and critical limb ischemia, Dopheide and coworkers25 showed that blood cDC numbers were increased, whereas pDC numbers were reduced in patients who had peripheral arterial disease in comparison with healthy controls. Of note, both cDCs and pDCs from patients who have critical limb ischemia revealed an immature phenotype, suggesting that severe ischemia and prolonged inflammation in this ailment might lead to an attenuation in the proinflammatory membrane patterns of circulating DC subsets.In general, most patient studies show declined blood DC numbers in CAD patients. Inconsistent results may be explained by differences in the extent and localization of disease, the timing of blood sampling (before/after a surgical intervention; lesion onset versus progression), the prevalence of risk factors across the patients included in these studies, and the cohort sizes consulted.Nevertheless, the actual cause for reduced circulating DC numbers remains unaddressed. One possibility for the decrease in circulating DCs might be their enhanced recruitment to the disease site (hence, plaque or the ischemic heart).9 Alterations in circulating DCs have been described in other autoimmune diseases as well, such as systemic lupus erythematosus,26 where markedly lowered blood DC numbers correlated with an accumulation of activated DCs in the inflamed tissue. In analogy, DCs could well be recruited to secondary lymphoid organs to prime naïve T cells.27 Circulating oxidized low-density lipoprotein (oxLDL) or circulating immunocomplexes,28 but also ischemic tissue–derived DAMPs were seen to induce DC activation,29 thus promoting their extravasation to the spleen or lymph nodes. Actually, a recent study has shown in CAD patients a more mature phenotype on a minor subset of circulating CD11chigh (BDCA-1+) cDCs, and BDCA-2+ pDCs, represented by the upregulation of CD83, CD80, CD86, and CCR7.17,20 Dopheide and colleagues30 additionally represented that in vitro monocyte-derived DCs from CAD patients revealed an increased expression of costimulatory markers (CD40, CD80, CD86) in comparison with healthy controls. However, it has to be acknowledged that monocyte-derived and classical DCs represent separate subsets, in that the transcriptional signature of monocyte-derived DCs is more reminiscent of that of macrophages than of classical DCs.31 Conceivably, these blood DC subsets exert distinct functions, and should be considered apart. Second, the apparent blood DC depletion could however also be explained by increased DC turnover, because of increased circulating cholesterol levels. Indeed, Alderman and colleagues32 have demonstrated in vitro that high concentrations of oxLDL provoke DC apoptosis. Otherwise, declines in DC numbers could be a temporary response to acute ischemia. Third, reduced blood DC numbers might also result from decreased release from bone marrow. Interestingly, the group of Bult has shown diminished plasma levels of FMS-like tyrosine kinase 3 ligand in CAD patients, a growth factor that is responsible for DC differentiation and release from bone marrow.20 Fourth, the altered blood DC abundance, phenotype, and function could be owing to CAD patient’s medication, including aspirin, statins, β-blockers, and angiotensin-converting enzyme inhibitors. Although supported by several in vitro studies,33–36 the validity of this notion needs further investigation.Recapitulating, circulating DC decline cannot be exclusively linked to the compartmentalization of this subset, be it to atherosclerotic plaque or lymphoid organs, because other covariates may modify blood DC numbers and functionality as well. This needs to be further addressed in future studies. Moreover, these observational studies leave unaddressed whether DCs are active contributors or just casual bystanders.DC Involvement in Vascular Inflammatory ProcessesBeside their presence in atherosclerosis, DC attendance has been described in other chronic inflammatory vasculopathies, such as giant cell arteritis, Takayasu arteritis, and Kawasaki disease.37–39 It is hypothesized that they contribute to the first critical steps in disease pathogenesis through breakdown of vascular tolerance. In these vasculopathies, resident DCs are located in the adventitia and adventitia-media border, and cDC numbers are seen to increase with disease progression.39 Dense infiltrates of mature cDCs and T cells have been described at later stages as well, reflective of DC-initiated, antigen-specific immune responses. Considering that DC networks are present in healthy arteries and that they function as professional APCs, they might well be involved in disease onset and progression through the presentation of modified (self-) antigens to T cells. The actual triggers to activate vascular DCs are yet unknown, as is their relative contribution to immune priming in comparison with other vascular resident APCs such as macrophages. Additionally, the recent comparative analysis of the transcriptional network of DC versus macrophage lineages has helped to redefine DC-specific molecular signatures in lymphoid and nonlymphoid tissues, allowing a better discrimination between DC subsets and macrophages.31 These novel insights will help to appreciate whether DCs, described in vasculature,6 are bona fide DCs or tissue resident macrophages. Altogether, a functional role for DCs in the pathogenesis of these diverse inflammatory vasculopathies remains to be established, because studies are of a rather descriptive nature.Functional Role for cDCs in AtherosclerosisIn human atherosclerotic plaques, fully mature DCs (CD83+ CD86+) accumulate within the rupture-prone atherosclerotic plaque shoulder where they produce T-cell chemotactic (CCL19 and CCL21) and proinflammatory cytokines (interleukin-12 [IL-12], IL-23, and tumor necrosis factor α [TNF-α]).40 Mapping of plaque-residing DCs revealed a close contact between DCs and activated T and natural killer T cells, suggesting that DCs tune or even orchestrate immune responses relevant to atherosclerosis.40 Of note, many of the histology studies are thwarted by the moderate/poor specificity of most DC markers, rendering the immunohistochemical detection of DCs a delicate issue. In fact, CD11c, an established DC marker regularly used to detect classical DCs within the atherosclerotic lesions, is also expressed on a wide scope of cells including tissue macrophages, natural killer cells, natural killer T cells, and a subset of T and B cells.14 Actually, all available cDC surface markers fail to conclusively identify this subset by immunohistochemistry. To circumvent this pitfall, the use of more refined or additional techniques, such as flow cytometric cell isolation, with the use of a panel of monocytic and DC surface markers, including CD11c, CD11b, F4/80, MerTK, CD64, Ly6C, is recommended to better appreciate DC presence and phenotype in different stages of atherosclerosis. Otherwise, DCs could be isolated by flow cytometry cell sorting for subsequent signature mapping (whole-genome arraying).Mouse models have been very insightful in elucidating DC functions in atherosclerosis. For instance, lipid accumulation in the initial stages of atherosclerosis was recently shown to be directed and regulated by intimal CD11c+ DCs, residing in the atherosclerotic-prone lesser curvature of the aortic arch.41 As already discussed above, the combined expression of CD68 and CD11c by these vascular resident DCs may be suggestive of a macrophage rather than bona fide DC phenotype, a notion that requires further validation.The impact of lipid uptake by DCs on their functionality remains a controversial subject. Dyslipidemia was seen to lead to an accumulation of DCs and macrophages within the atherosclerotic plaque.42,43 As reported in several studies, hyperlipidemic conditions and direct exposure of (splenic) CD11c+ cDCs to (oxidized) lipoproteins did not seem to impact their antigen-presentation and T-cell priming ability.44,45 In a transgenic mouse model with CD11c+ driven overexpression of the antiapoptotic gene hBcl-2, the extended lifespan and enhanced immunogenicity of circulating cDCs was associated with augmented T-cell priming, elevated levels of T helper 1 (Th1) and Th17 cytokines, and increased production of Th1-driven IgG2c antibodies under hyperlipidemic conditions.44 This major functional DC expansion did not aggravate lesion formation, because it was compensated for by decreased plasma cholesterol levels. Further support for a link between DC function and lipid metabolism was derived from the augmented plasma cholesterol levels after cDC depletion in hyperlipidemic ApoE−/− crossed to CD11c diphtheria toxin receptor (CD11c-DTR) transgenic mice.44 However, data acquired in this study have to be interpreted cautiously because CD11c is also expressed by several other lineages, and CD11c-DTR–based depletion will affect other subsets as well.46 In contrast to the above studies, Kopf and coworkers have shown that dyslipidemia did affect cDCs in vitro and in vivo, herein the CD8α− cDC subset, by impairing their response to Toll-like receptor (TLR) stimulation during Leishmania major infection. OxLDL appeared to be directly responsible for this effect, because it uncoupled TLR-mediated signaling in splenic cDCs, dampening DC activation and Th1 responses.47 Whether or not these findings also apply for humans remains to be addressed.Next to classical lymphoid-resident and blood circulating cDC subsets, several studies have examined the impact of oxLDL on monocyte-derived DCs, which is of relevance because a majority of intimal DCs are thought to originate from monocytes.6 In vitro exposure to oxLDL during differentiation of human monocytes with granulocyte-macrophage colony-stimulating factor resulted in phenotypically mature DCs with upregulated HLA-DR, CD40, and CD86 and induced capacity to T-cell activation.32,48 However, incubation with high concentrations of oxLDL attenuated DC function and induced apoptosis.32 This may in part be associated with the strong oxLDL-induced downregulation of CCR7 and its ligand CCL21 by monocyte-derived DCs, which likely will impact their migratory capacity to and in plaque.49 It will be of interest to investigate and compare the effect of (modified) lipoproteins on in vitro FMS-like tyrosine kinase 3 ligand–cultured DCs, because they represent the classical in vivo equivalents. In contrast to the above-described data, Blueml and colleagues50 have shown that oxidized phospholipids impair monocyte-derived DC maturation by blocking TLR3- and TLR4-mediated upregulation of costimulatory molecules and induction of proinflammatory cytokines in human DCs.Taken together, considerable controversy exists on DC subset function(s) in hyperlipidemia-associated atherosclerosis, which is fostered among others by the apparent promiscuous expression patterns of alleged DC markers and the significant plasticity of both DCs and macrophages. But the definition of transcriptional DC versus macrophage signatures will undoubtedly help to reassess the actual presence of bona fide resident DCs within the vasculature.29,51 Additionally, it will be of importance to uncover how early and more advanced stages of hyperlipidemia impair DC (precursor) homeostasis, including their development in the bone marrow, DC mobilization into the circulation, peripheral phenotype, and migratory routes. In addition, extensive knowledge about DC actions within a lipid-rich environment such as the atherosclerotic plaque is lacking. How lipid uptake and prolonged intracellular storage interfere with signaling pathways responsible for DC activation is still controversial and will require further study.A Functional Role for Plasmacytoid DCs in AtherosclerosisThe group of Weyand and coworkers52 has recently shown the presence of CD123+ pDCs in human carotid atherosclerotic plaques, mainly located in the shoulder region that was also enriched in interferon-α (IFN-α) positive cells, thus associating pDC presence with IFN-α production. Furthermore, pDC numbers were significantly increased in unstable in comparison with stable human lesions. In vitro CpG-induced IFN-α release by pDCs induced a 10-fold upregulation of tumor necrosis factor-related apoptosis-inducing ligand expression on CD4+ T cells, thus promoting apoptosis of vascular smooth muscle cells and endothelial cells, processes that tremendously contribute to plaque destabilization.52 However, these data leave unaddressed whether pDCs are functional in the atherosclerotic plaque in vivo. We and others have recently shown that CD123 displays only moderate specificity for human pDCs, being colocalized also with CD68+ macrophages and with ASMA+ vascular smooth muscle cells.9,53 Use of the human pDC-specific marker BDCA-4 by our group revealed the scanty and equivalent presence of pDCs in human stable and unstable plaques. Moreover, we demonstrated that expression of IFN-α in human unstable versus stable carotid endarterectomy tissue specimens did not differ, suggesting that in chronic low-grade inflammatory processes, such as atherosclerosis, pDC activation may not be a prominent feature.53Our group has recently shown that selective depletion of pDCs by 120G8 monoclonal antibody administration in Ldlr−/− mice fed a high-fat diet exacerbated lesion size in the carotid artery and the aortic roots, and promoted plaque T-cell accumulation and peripheral CD4+ T cell activation, as well. pDCs isolated from atherosclerotic mice suppressed CD4+ T-cell proliferation in an indoleamine-2,3-dioxygenase–dependent manner, suggestive of an atheroprotective role for pDCs in atherosclerosis.53 In contrast to our study, Döring and colleagues28 and MacRitchie and colleagues,54 as well, reported significantly decreased diet-induced lesion formation in the aortic root and the aorta of pDC-depleted ApoE−/− mice, whereas plaques showed a more stable phenotype. Both groups investigated the impact of pDC depletion by use of the PDCA-1 depletion antibody on early lesion development (4 weeks of high-fat diet feeding). These controversial findings are intriguing. A seeming paradox was in the presence of pDCs in the atherosclerotic plaque. Whereas pDCs could barely be detected in mouse atherosclerotic lesions in Ldlr−/− mice,53 they were detected in lesions of ApoE−/− mice, mainly in the plaque shoulder, at which pDC abundance was increased with high-fat diet feeding and lesion progression.28 Conversely, MacRitchie and colleagues54 described the constitutive presence of mostly immature pDCs in noninflamed aortic tissue of normolipidemic mice, at numbers similar to those seen in atherosclerotic ApoE−/− mice. Nevertheless, the antigen presentation capacity of aortic pDCs from ApoE−/− mice was enhanced. In line with this, Döring and colleagues28 showed that sorted aortic pDCs from hyperlipidemic mice, ex vivo primed, were capable of triggering T-cell stimulation in vivo. Finally, baseline IFN-α levels were below detection levels or not affected by pDCs in our study and the study of MacRitchie and coworkers,53,54 whereas Döring and colleagues28 demonstrated elevated IFN-α levels in plaque (mRNA) and serum in high-fat diet–fed ApoE−/− mice, being reduced after pDC depletion. It must be noted that these groups used different methodologies, such as the use of the depletion antibody, administration regimen, and mouse models. For example, the ApoE−/− model displays more aggressive atherosclerosis than the Ldlr−/− model, which may favor pDCs switching to an immunogenic mode. The use of pDC depletion antibodies (120G8, mPDCA-1 or 927) targeting BST2 has been shown to eliminate pDCs quite efficiently.55 BST-2 is restricted to pDCs in the steady state. Bst-2 expression was, at transcriptional level, reported to be induced on other cell subsets on type I IFN stimulation, albeit still markedly lower than that of pDCs. Nevertheless, in the context of atherosclerosis, we,53 Döring and colleagues,28 and MacRitchie and colleagues,54 as well, demonstrated the specific depletion of pDCs by Bst-2–specific monoclonal antibody, thus excluding undesired side effects due to nonspecific depletion.Regarding the complex pathophysiology of atherosclerosis, pDCs could well exert dual functions in early and advanced stages of disease, dependent on their microenvironmental context. During episodes of fulminant plaque inflammation pDCs acquire proatherogenic functions by rapid secretion of type I IFNs and proinflammatory cytokines, whereas, during low grade chronic inflammatory stages, pDCs may act tolerogenic by inhibiting proliferation of CD4+ T cells. Indeed, pDCs are involved in the pathogenesis of a range of autoimmune diseases characterized by a type I IFN signature,56 whereas alternatively activated pDCs are considered to contribute to tolerance induction.56 Further studies are warranted to elucidate the actual pathways that are activated in pDCs during different stages of atherosclerosis by using more advanced animal models, such as conditional E2-2 knockout.56,57 Nevertheless, these findings clearly identify this cell type as an interesting new target for future therapeutic intervention studies in the treatment of atherosclerosis.CVD Risk Factors: Contribution of DCs?Type 2 diabetes mellitus (T2D) and hypertension are major risk factors for the development of atherosclerosis and its cardiovascular complications. Chronic inflammation is thought to accelerate the progression of these pathological conditions.58,59 DCs are likely to contribute here by triggering cell-mediated immune responses. The next 2 sections outline the current knowledge on potential DC functions in T2D and hypertension.A Role for DCs in T2D Patients With Atherosclerotic ComplicationsInsulin resistance and hyperglycemia in T2D are associated with a systemic proinflammatory state (increase in proinflammatory cytokines such as IL-6, activation of immune cells) that facilitates the development of atherosclerosis.60 In vitro studies have shown that advanced glycosylation end products61 and hyperinsulinemia62 enhance DC maturation and induce an antigen-specific T-cell activation, thus supporting a contributory role of DC (subsets) on the immune reactions in diabetic atherosclerosis. Yao and colleagues63 recently reported a significant decline in circulating cDCs in T2D patients with unstable angina pectoris versus healthy controls and T2D patients, whereas pDC numbers remained mainly altered. cDCs showed a more mature and activated phenotype, evidenced by the upregulation of CD86 and the enhanced capability to stimulate T-cell proliferation in vitro. Reduced circulating DC numbers in T2D patients with atherosclerotic complications was attributed to an increased trafficking into the inflamed vulnerable plaque or to neighboring lymph nodes, because patients had significantly increased levels of fractalkine, a chemokine that is mainly involved in the recruitment of Ly6Clow monocytes to sites of inflammation, but has thus far not been linked to classical DC chemotaxis.64 In contrast to these findings, Orfao and coworkers65 showed both quantitatively and functionally impaired proinflammatory cytokine response by circulating DCs from T2D patients with atherosclerotic complications. Conceivably, the increased plasma TNF-α levels observed in patients with diabetic atherosclerosis may underlie this impairment, because it can tone blood DC differentiation.66 This notion is encouraged by studies describing an inverse correlation between blood DC numbers and plasma TNF-α concentrations in T2D.67,68 Of note, medication used for glycemic control and for the treatment of diabetes-related comorbidities (angiotensin-converting enzyme antagonists, angiotensin receptor blockers, or statins) could be partly causal in the altered blood DC abundance.59 Altogether, although DC function is clearly perturbed in T2D, the present state of knowledge does not allow segregating atherosclerosis from T2D intrinsic DC effects.A Role for DCs in HypertensionT cells have been described to contribute to hypertension,69 a process that likely involves their priming by APCs, such as DCs, with the capacity to present neoepitopes, generated by necrotic and apoptotic cells.58 However, less is known regarding the role of DCs in hypertension. DC accumulation in alveolar lesions of human and experimental pulmonary arterial hypertension has been described.70 Recently, Vinh and colleagues71 showed that the CD28-blocking agent abatacept prevents angiotensin II–induced hypertension in mice, supporting a contributory role for DCs as APCs in hypertension. Additionally, they observed increased activated DC numbers in spleen and lymph nodes of hypertensive mice.71 However, these data leave unaddressed whether DCs are the primary cell type responsible for antigen presentation. The more abundant vascular macrophages in the vessel wall might as well function as APCs. Interestingly, the renin-angiotensin-aldosterone system can by itself initiate/modulate innate and adaptive immune responses and inflict target-organ damage as shown by the group of Mueller and coworkers58 in a compound transgenic rat model harboring human renin/angiotensin genes. Activation of the angiotensin-IA receptor—among others