Plasma NOTCH3 and the risk of cardiovascular recurrence in patients with ischemic stroke.

Background: Ischemic stroke patients are more prone to developing another cardiovascular event.

Aim: This study aims to examine potential biological predispositions to cardiovascular recurrence in patients with ischemic stroke.

Design: Human and preclinical studies.

Relative deficiency in interferon-γ-secreting CD4+ T cells is strongly associated with poorer COVID-19 vaccination responses in older adults.

Although the two-dose mRNA vaccination regime provides protection against SARS-CoV-2, older adults have been shown to exhibit poorer vaccination responses. In addition, the role of vaccine-induced T-cell responses is not well characterised. We aim to assess the impact of age on immune responses after two doses of the BNT162b2 mRNA vaccine, focussing on antigen-specific T-cells.

Deterministic reprogramming of neutrophils within tumors.

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1 state.

iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development.

Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability.

Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake.

Biomechanical control of lymphatic vessel physiology and functions.

The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in tissue fluid homeostasis, immunosurveillance, lipid metabolism and inflammation. It is therefore not surprising that the list of human diseases associated with lymphatic malfunctions has grown larger, including issues beyond lymphedema, a pathology traditionally associated with lymphatic drainage insufficiency. Thus, the discovery of factors and pathways that can promote optimal lymphatic functions may offer new therapeutic options.

Network analysis of large-scale ImmGen and Tabula Muris datasets highlights metabolic diversity of tissue mononuclear phagocytes.

The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets: we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues; (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples); and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles.

Multiple aspects of lymphatic dysfunction in an mouse model of hypercholesterolemia.

Rodent models of cardiovascular disease have uncovered various types of lymphatic vessel dysfunction that occur in association with atherosclerosis, type II diabetes and obesity. Previously, we presented evidence for impaired lymphatic drainage in apolipoprotein E null ( ) mice fed a high fat diet (HFD). Whether this impairment relates to the dysfunction of collecting lymphatics remains an open question.

Vascular smooth muscle cells in low SYNTAX scores coronary artery disease exhibit proinflammatory transcripts and proteins correlated with IL1B activation.

Background And Aims: The SYNTAX score is clinically validated to stratify number of lesions and pattern of CAD. A better understanding of the underlying molecular mechanisms influencing the pattern and complexity of coronary arteries lesions among CAD patients is needed.

Methods: Human arterial biopsies from 49 patients (16 low-SYNTAX-score (LSS, <23), 16 intermediate-SYNTAX-score (ISS, 23 to 32) and 17 high-SYNTAX-score (HSS, >32)) were evaluated using Affymetrix GeneChip® Human Genome U133 Plus 2.

Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions.

Protein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 (Spns2) has been shown to reduce disease severity in several autoimmune disease models. To examine whether Spns2 could be exploited as a drug target, we generated and characterized the mice with postnatal knockout of Spns2 (Spns2-Mx1Cre).

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways.

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta =  - 1.

Transitional premonocytes emerge in the periphery for host defense against bacterial infections.

Circulating Ly6C monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6C monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis.

Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy.

Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying this effect is unknown. Here, we demonstrated that caffeine decreased VSMC proliferation and induced macroautophagy/autophagy in an vascular injury model of restenosis.

Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis.

The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown. Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery.

Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis.

In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide.

cGAS-STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells.

Deficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonists and failed to induce type I interferon (IFN) expression in many tested human tumor cells including DU145 prostate cancer cells.

LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection.

Group A Streptococcus (GAS) causes diverse human diseases, including life-threatening soft-tissue infections. It is accepted that the human antimicrobial peptide LL-37 protects the host by killing GAS. Here, we show that GAS extracellular protease ScpC N-terminally cleaves LL-37 into two fragments of 8 and 29 amino acids, preserving its bactericidal activity.

Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe.

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe.

The Unresolved Pathophysiology of Lymphedema.

Lymphedema is the clinical manifestation of impaired lymphatic transport. It remains an under-recognized and under-documented clinical condition that still lacks a cure. Despite the substantial advances in the understanding of lymphatic vessel biology and function in the past two decades, there are still unsolved questions regarding the pathophysiology of lymphedema, especially in humans.

The indirect antiangiogenic effect of IL-37 in the tumor microenvironment.

IL-37, a newly identified IL-1 family cytokine, has been shown to play an important role in inflammatory diseases, autoimmune diseases, and carcinogenesis. IL-37 has been suggested to suppress tumoral angiogenesis, whereas some publications showed that IL-37 promoted angiogenesis through TGF-β signaling in both physiologic and pathologic conditions. Therefore, the function of IL-37 in tumoral angiogenesis is not clear and the underlying mechanism is not known.

Cavity Macrophages Get to the Heart of the Issue.

In this issue of Immunity, Deniset et al. (2019) reveal a reparative function for GATA6 pericardial cavity macrophages following cardiac injury. Their findings call for reconsideration of surgical procedures that involve the removal of the pericardium.

Protective Function of Mitogen-Activated Protein Kinase Phosphatase 5 in Aging- and Diet-Induced Hepatic Steatosis and Steatohepatitis.

Nonalcoholic fatty liver disease is currently the most common liver disease and is a leading cause of liver-related morbidity and mortality. However, its pathogenesis remains largely unclear. We previously showed that mice deficient in mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) spontaneously developed insulin resistance and glucose intolerance, which are associated with visceral obesity and adipose tissue inflammation.