Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr mice.

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated.

Resident Memory T Cells in the Atherosclerotic Lesion Associate With Reduced Macrophage Content and Increased Lesion Stability.

Background: Tissue resident memory T (T) cells are a T-cell subset that resides at the site of prior antigen recognition to protect the body against reoccurring encounters. Besides their protective function, T cells have also been implicated in inflammatory disorders. T cells are characterized by the expression of CD69 and transcription factors Hobit (homolog of Blimp-1 [B lymphocyte-induced maturation protein 1] in T cells) and Blimp-1.

Virus-Associated CD8 T-Cells Are Not Activated Through Antigen-Mediated Interaction Inside Atherosclerotic Lesions.

Introduction: Viral infections have been associated with the progression of atherosclerosis and CD8 T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8 T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8 T-cells in the atherosclerotic lesion.

Single-cell profiling reveals age-associated immunity in atherosclerosis.

Aims: Aging is a dominant driver of atherosclerosis and induces a series of immunological alterations, called immunosenescence. Given the demographic shift towards elderly, elucidating the unknown impact of aging on the immunological landscape in atherosclerosis is highly relevant. While the young Western diet-fed Ldlr-deficient (Ldlr-/-) mouse is a widely used model to study atherosclerosis, it does not reflect the gradual plaque progression in the context of an aging immune system as occurs in humans.

Single-cell T cell receptor sequencing of paired human atherosclerotic plaques and blood reveals autoimmune-like features of expanded effector T cells.

Atherosclerosis is a lipid-driven chronic inflammatory disease; however, whether it can be classified as an autoimmune disease remains unclear. In this study, we applied single-cell T cell receptor seqencing (scTCR-seq) on human carotid artery plaques and matched peripheral blood mononuclear cell samples to assess the extent of TCR clonality and antigen-specific activation within the various T cell subsets. We observed the highest degree of plaque-specific clonal expansion in effector CD4 T cells, and these clonally expanded T cells expressed genes such as , and , indicative of recent TCR engagement, suggesting antigen-specific stimulation.

B- and T-lymphocyte attenuator stimulation protects against atherosclerosis by regulating follicular B cells.

Aims: The immune system is strongly involved in atherosclerosis and immune regulation generally leads to attenuated atherosclerosis. B- and T-lymphocyte attenuator (BTLA) is a novel co-receptor that negatively regulates the activation of B and T cells; however, there have been no reports of BTLA and its function in atherosclerosis or cardiovascular disease (CVD). We aimed to assess the dominant BTLA expressing leucocyte in CVD patients and to investigate whether BTLA has a functional role in experimental atherosclerosis.

CD39 identifies a microenvironment-specific anti-inflammatory CD8 T-cell population in atherosclerotic lesions.

Background And Aims: CD8 T-cells have been attributed both atherogenic and atheroprotective properties, but analysis of CD8 T-cells has mostly been restricted to the circulation and secondary lymphoid organs. The atherosclerotic lesion, however, is a complex microenvironment containing a plethora of inflammatory signals, which may affect CD8 T-cell activation. Here, we address how this environment affects the functionality of CD8 T-cells.

Flow Cytometry-Based Characterization of Mast Cells in Human Atherosclerosis.

The presence of mast cells in human atherosclerotic plaques has been associated with adverse cardiovascular events. Mast cell activation, through the classical antigen sensitized-IgE binding to their characteristic Fcε-receptor, causes the release of their cytoplasmic granules. These granules are filled with neutral proteases such as tryptase, but also with histamine and pro-inflammatory mediators.

Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization.

Mast cells accumulate in the perivascular tissue during atherosclerotic plaque progression and contribute to plaque destabilization. However, the specific triggers for mast cell activation in atherosclerosis remain unresolved. We hypothesized that psychological stress-induced activation of mast cells may contribute to plaque destabilization.

Hypercholesterolemia Induces a Mast Cell-CD4 T Cell Interaction in Atherosclerosis.

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 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.

CD8+ T-cells contribute to lesion stabilization in advanced atherosclerosis by limiting macrophage content and CD4+ T-cell responses.

Aims: 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.

Methods And Results: Human endarterectomy samples analysed 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.

Inhibition of 14q32 microRNA miR-495 reduces lesion formation, intimal hyperplasia and plasma cholesterol levels in experimental restenosis.

Background And Aims: We aimed at investigating the role of 14q32 microRNAs in intimal hyperplasia and accelerated atherosclerosis; two major contributors to restenosis. Restenosis occurs regularly in patients treated for coronary artery disease and peripheral arterial disease. We have previously shown that inhibition of 14q32 microRNAs leads to increased post-ischemic neovascularization, and microRNA miR-494 also decreased atherosclerosis, while increasing plaque stability.

Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model.

Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model.

Systematic Evaluation of the Cellular Innate Immune Response During the Process of Human Atherosclerosis.

Background: The concept of innate immunity is well recognized within the spectrum of atherosclerosis, which is primarily dictated by macrophages. Although current insights to this process are largely based on murine models, there are fundamental differences in the atherosclerotic microenvironment and associated inflammatory response relative to humans. In this light, we characterized the cellular aspects of innate immune response in normal, nonprogressive, and progressive human atherosclerotic plaques.

Mast cell depletion in the preclinical phase of collagen-induced arthritis reduces clinical outcome by lowering the inflammatory cytokine profile.

Background: Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, which is characterized by inflammation of synovial joints leading to the destruction of cartilage and bone. Infiltrating mast cells can be found within the inflamed synovial tissue, however their role in disease pathogenesis is unclear. Therefore we have studied the role of mast cells during different phases of experimental arthritis.

Deficiency of the TLR4 analogue RP105 aggravates vein graft disease by inducing a pro-inflammatory response.

Venous grafts are often used to bypass occlusive atherosclerotic lesions; however, poor patency leads to vein graft disease. Deficiency of TLR4, an inflammatory regulator, reduces vein graft disease. Here, we investigate the effects of the accessory molecule and TLR4 analogue RadioProtective 105 (RP105) on vein graft disease.

Inhibition of MicroRNA-494 Reduces Carotid Artery Atherosclerotic Lesion Development and Increases Plaque Stability.

Objectives: Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery.

Background: We made a selection of 164 genes involved in atherosclerosis.

Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression.

Aims: Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression.

Methods And Results: Systemic IgE-mediated mast cell activation in apoE(-/-)μMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions.

RP105 deficiency attenuates early atherosclerosis via decreased monocyte influx in a CCR2 dependent manner.

Objective: Toll like receptor 4 (TLR4) plays a key role in inflammation and previously it was established that TLR4 deficiency attenuates atherosclerosis. RadioProtective 105 (RP105) is a structural homolog of TLR4 and an important regulator of TLR4 signaling, suggesting that RP105 may also be an important effector in atherosclerosis. We thus aimed to determine the role of RP105 in atherosclerotic lesion development using RP105 deficient mice on an atherosclerotic background.

Complement factor C5a induces atherosclerotic plaque disruptions.

Complement factor C5a and its receptor C5aR are expressed in vulnerable atherosclerotic plaques; however, a causal relation between C5a and plaque rupture has not been established yet. Accelerated atherosclerosis was induced by placing vein grafts in male apoE(-/-) mice. After 24 days, when advanced plaques had developed, C5a or PBS was applied locally at the lesion site in a pluronic gel.

TLR4 accessory molecule RP105 (CD180) regulates monocyte-driven arteriogenesis in a murine hind limb ischemia model.

Aims: We investigated the role of the TLR4-accessory molecule RP105 (CD180) in post-ischemic neovascularization, i.e. arteriogenesis and angiogenesis.

Vascular neuropeptide Y contributes to atherosclerotic plaque progression and perivascular mast cell activation.

Aim: Neuropeptide Y is an abundantly expressed neurotransmitter capable of modulating both immune and metabolic responses related to the development of atherosclerosis. NPY receptors are expressed by a number of vascular wall cell types, among which mast cells. However, the direct effects of NPY on atherosclerotic plaque development and progression remain to be investigated.

Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease.

Aims: Failure of vein graft conduits due to vein graft thickening, accelerated atherosclerosis, and subsequent plaque rupture is applicable to 50% of all vein grafts within 10 years. New potential therapeutic targets to treat vein graft disease may be found in components of the innate immune system, such as mast cells and complement factors, which are known to be involved in atherosclerosis and plaque destabilization. Interestingly, mast cells can be activated by complement factor C5a and, therefore, a direct role for C5a-mediated mast cell activation in vein graft disease is anticipated.