Crosstalk between dendritic cells and T lymphocytes during atherogenesis: Focus on antigen presentation and break of tolerance

Atherosclerosis is a chronic disease resulting from an impaired lipid and immune homeostasis, where the interaction between innate and adaptive immune cells leads to the promotion of atherosclerosis-associated immune-inflammatory response. Emerging evidence has suggested that this response presents similarities to the reactivity of effector immune cells toward self-epitopes, often as a consequence of a break of tolerance. In this context, dendritic cells, a heterogeneous population of antigen presenting cells, play a key role in instructing effector T cells to react against foreign antigens and T regulatory cells to maintain tolerance against self-antigens and/or to patrol for self-reactive effector T cells. Alterations in this delicate balance appears to contribute to atherogenesis. The aim of this review is to discuss different DC subsets, and their role in atherosclerosis as well as in T cell polarization. Moreover, we will discuss how loss of T cell tolerogenic phenotype participates to the immune-inflammatory response associated to atherosclerosis and how a better understanding of these mechanisms might result in designing immunomodulatory therapies targeting DC-T cell crosstalk for the treatment of atherosclerosis-related inflammation

Combination therapy in cholesterol reduction: focus on ezetimibe and statins

Although widely used in lipid lowering therapy, HMG CoA reductase inhibitors (even when administered at high doses) are frequently insufficient to achieve guideline-recommended LDL-C goals for many patients with hypercholesterolemia in everyday clinical practice. Many patients do not achieve LDL-C goal on the initial dose of statin and the majority of these patients does not reach their goal after 6 months. As a consequence, a wide therapeutic gap exists between target LDL-C levels and those typically achieved in clinical practice. A recent and more effective therapeutic hypocholesterolemic strategy is to treat the two main sources of cholesterol simultaneously (production of cholesterol, mainly in the liver, and absorption of cholesterol in the intestine) with a complementary mechanism of action, by co-administering ezetimibe, a novel agent inhibiting cholesterol absorption, with a statin, which inhibits cholesterol production in the liver. Ezetimibe can be effectively and safely co-administered with any dose of any statin and, compared with the single inhibition of cholesterol production, afforded by statins alone, provides consistently greater reductions in LDL-C through dual inhibition of both cholesterol production and absorption. We summarize the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using ezetimibe either alone or co-administered with statins in controlling elevated levels of plasma LDL cholesterol

LDL-Cholesterol-Lowering Therapy.

AbstractThe causal relation between elevated levels of LDL-C and cardiovascular disease has been largely established by experimental and clinical studies. Thus, the reduction of LDL-C levels is a major target for the prevention of cardiovascular disease. In the last decades, statins have been used as the main therapeutic approach to lower plasma cholesterol levels; however, the presence of residual lipid-related cardiovascular risk despite maximal statin therapy raised the need to develop additional lipid-lowering drugs to be used in combination with or in alternative to statins in patients intolerant to the treatment. Several new drugs have been approved which have mechanisms of action different from statins or impact on different lipoprotein classes

Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.

Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4+ T cells. Memory CD4+ T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4+ T cell differentiation into CD44hi-CCR7lo-CD62Llo-CXCR3+-LFA1+ effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4+ T cells and dendritic cells and was mediated via direct exposure of CD4+ T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming

Fatty acid metabolism complements glycolysis in th selective regulatory t cell expansion during tumor growth

The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs’ advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs’ expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment

Translational opportunities of single-cell biology in atherosclerosis

The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD

PITX2 gain-of-function mutation associated with atrial fibrillation alters mitochondrial activity in human iPSC atrial-like cardiomyocytes

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide; however, the underlying causes of AF initiation are still poorly understood, particularly because currently available models do not allow in distinguishing the initial causes from maladaptive remodeling that induces and perpetuates AF. Lately, the genetic background has been proven to be important in the AF onset. iPSC-derived cardiomyocytes, being patient- and mutation-specific, may help solve this diatribe by showing the initial cell-autonomous changes underlying the development of the disease. Transcription factor paired-like homeodomain 2 (PITX2) has been identified as a key regulator of atrial development/differentiation, and the PITX2 genomic locus has the highest association with paroxysmal AF. PITX2 influences mitochondrial activity, and alterations in either its expression or function have been widely associated with AF. In this work, we investigate the activity of mitochondria in iPSC-derived atrial cardiomyocytes (aCMs) obtained from a young patient (24 years old) with paroxysmal AF, carrying a gain-of-function mutation in PITX2 (rs138163892) and from its isogenic control (CTRL) in which the heterozygous point mutation has been reverted to WT. PITX2 aCMs show a higher mitochondrial content, increased mitochondrial activity, and superoxide production under basal conditions when compared to CTRL aCMs. However, increasing mitochondrial workload by FCCP or β-adrenergic stimulation allows us to unmask mitochondrial defects in PITX2 aCMs, which are incapable of responding efficiently to the higher energy demand, determining ATP deficiency

Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues

: Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases

The glucose transporter 2 regulates CD8⁺ T cell function via environment sensing

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation

T follicular helper cells promote a beneficial gut ecosystem for host metabolic homeostasis by sensing microbiota-derived extracellular ATP

The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer’s patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis. The results of this study indicate that Tfh cells play a role in host-microbiota mutualism beyond protecting the intestinal mucosa by induction of affinity-matured IgA and suggest that extracellular ATP constitutes an inter-kingdom signaling molecule important for selecting a beneficial microbial community for the host via P2X7-mediated regulation of B cell help