β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection.

Light deficiency in Apoe-/-mice increases atheroma plaque size and vulnerability by modulating local immunity.

Previous research suggests a potential involvement of the cytokine LIGHT (TNFSF14) in atherosclerosis. In this study, the genetic inactivation of Light in Apolipoprotein E deficient mice (male and female C57BL) augmented plaque size and vulnerability while decreasing Treg cells. Human and mouse transcriptomic results demonstrated deranged immune pathways in human atheromas with low LIGHT expression levels and in Light-deficient murine atheromas.

Neutrophils-biology and diversity.

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity.

Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin β receptor and the tumor necrosis factor receptor.

Objective: Vascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied.

Material And Methods: Human aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTα), the heterotrimer LTαβ or with vehicle for 72h.

Neutrophils in chronic inflammatory diseases.

Chronic inflammation is a component of many disease conditions that affect a large group of individuals worldwide. Chronic inflammation is characterized by persistent, low-grade inflammation and is increased in the aging population. Neutrophils are normally the first responders to acute inflammation and contribute to the resolution of inflammation.

Dissecting Abdominal Aortic Aneurysm Is Aggravated by Genetic Inactivation of LIGHT (TNFSF14).

Abdominal aortic aneurysm (AAA), is a complex disorder characterized by vascular vessel wall remodeling. LIGHT (TNFSF14) is a proinflammatory cytokine associated with vascular disease. In the present study, the impact of genetic inactivation of was investigated in dissecting AAA induced by angiotensin II (AngII) in the Apolipoprotein E-deficient () mice.

Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia.

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD.

Dapagliflozin Does Not Modulate Atherosclerosis in Mice with Insulin Resistance.

Type 2 diabetes mellitus (T2DM) increases morbimortality in humans via enhanced susceptibility to cardiovascular disease (CVD). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are drugs designed for T2DM treatment to diminish hyperglycaemia by reducing up to 90% of renal tube glucose reabsorption. Clinical studies also suggest a beneficial action of SGLT2i in heart failure and CVD independent of its hypoglycaemiant effect.

TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity.

Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice.

Type 1 diabetic mellitus patients with increased atherosclerosis risk display decreased CDKN2A/2B/2BAS gene expression in leukocytes.

Background: Type 1 diabetes mellitus (T1DM) patients display increased risk of cardiovascular disease (CVD) and are characterized by a diminished regulatory T (Treg) cell content or function. Previous studies have shown an association between decreased CDKN2A/2B/2BAS gene expression and enhanced CVD. In the present study the potential relationship between CDKN2A/2B/2BAS gene expression, immune cell dysfunction and increased cardiovascular risk in T1DM patients was explored.

Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus.

Previous studies indicate a role of CDKN2A/2B/2BAS genes in atherosclerosis and type 2 diabetes mellitus (T2DM). Progression of these diseases is accompanied by T-cell imbalance and chronic inflammation. Our main objective was to investigate a potential association between CDKN2A/2B/2BAS gene expression and T cell phenotype in T2DM and coronary artery disease (CAD) in humans, and to explore the therapeutic potential of these genes to restore immune cell homeostasis and disease progression.

Understanding the Impact of Dietary Cholesterol on Chronic Metabolic Diseases through Studies in Rodent Models.

The development of certain chronic metabolic diseases has been attributed to elevated levels of dietary cholesterol. However, decades of research in animal models and humans have demonstrated a high complexity with respect to the impact of dietary cholesterol on the progression of these diseases. Thus, recent investigations in non-alcoholic fatty liver disease (NAFLD) point to dietary cholesterol as a key factor for the activation of inflammatory pathways underlying the transition from NAFLD to non-alcoholic steatohepatitis (NASH) and to hepatic carcinoma.

The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype.

Aims/hypothesis: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated.

Methods: Atherosclerosis development was evaluated in Apoe Irs2 mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide.

Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIGHT/Lymphotoxin β-Receptor pathway.

Coexistence of insulin resistance (IR) and metabolic syndrome (MetS) increases the risk of cardiovascular disease (CVD). Genetic studies in diabetes have linked Hepatic Lipase (HL) to an enhanced risk of CVD while others indicate a role of HL in inflammatory cells. Thus, we explored the role of HL on atherosclerosis and inflammation in a mouse model of MetS/IR, (apoE-/-Irs2+/- mice) and in patients with MetS and IR.

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis.

Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels.

Ink4/Arf locus restores glucose tolerance and insulin sensitivity by reducing hepatic steatosis and inflammation in mice with impaired IRS2-dependent signalling.

Single nucleotide polymorphisms near the Ink4/Arf locus have been associated with type-2 diabetes mellitus. Previous studies indicate a protective role of the locus in the carbohydrate metabolism derangement associated with ageing in wild-type mice. The present study demonstrates that the increased Ink4/Arf locus expression in 1-year-old mice, partially-deficient for the insulin receptor substrate (IRS)2 (Irs2+/-SuperInk4/Arf mice) ameliorates hepatic steatosis, inflammation and insulin resistance.