Haematometabolism rewiring in atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular diseases are the most frequent cause of death worldwide. The clinical complications of atherosclerosis are closely linked to the haematopoietic and immune systems, which maintain homeostatic functions and vital processes in the body. The nodes linking metabolism and inflammation are receiving increasing attention because they are inextricably linked to inflammatory manifestations of non-communicable diseases, including atherosclerosis.

GLS2 links glutamine metabolism and atherosclerosis by remodeling artery walls.

Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients with cardiovascular diseases, but the underlying mechanisms remain largely unknown. Using the human MESA cohort, here we show that plasma glutamine-glutamate ratio is an independent risk factor for carotid plaque progression. Mice deficient in glutaminase-2 (Gls2), the enzyme that mediates hepatic glutaminolysis, developed accelerated atherosclerosis and susceptibility to catastrophic cardiac events, while Gls2 overexpression partially protected from disease progression.

Fructooligosaccharides benefits on glucose homeostasis upon high-fat diet feeding require type 2 conventional dendritic cells.

Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity.

Further knowledge and developments in resistance mechanisms to immune checkpoint inhibitors.

The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular immune-checkpoint inhibitors (ICIs). These immunotherapies release the host's immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable, such as metastatic melanoma, metastatic renal cell carcinoma (RCC), microsatellite instability (MSI) high colorectal cancer and late stages of non-small cell lung cancer (NSCLC). However, about 80% of the patients fail to respond to these immunotherapies and are therefore left with other less effective and potentially toxic treatments.

Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death.

The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to β-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving β-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production.

Cholesterol efflux pathways hinder KRAS-driven lung tumor progenitor cell expansion.

Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRAS mutation with specific disruption of cholesterol efflux pathways in epithelial progenitor cells promoted tumor growth. Defective cholesterol efflux in epithelial progenitor cells governed their transcriptional landscape to support their expansion and create a pro-tolerogenic tumor microenvironment (TME).

Inflamed macrophages sans mitochondrial pyruvate carrier?

Glycolysis provides building blocks for the proinflammatory activation of macrophages and simultaneously generates pyruvate. In this issue of , Ran et al. provide evidence that the transport of pyruvate to fuel the Krebs cycle in the mitochondria is not required in the inflammatory response.

Host genetic variability and determinants of severe COVID-19.

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, convergent studies have provided evidence that host genetic background may contribute to the development of severe coronavirus disease (COVID-19). Here, we summarize how some genetic variations, such as in SARS-CoV-2 receptor angiotensin-converting enzyme 2 or interferon signaling pathway, may help to understand why some individuals can develop severe COVID-19.

T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice.

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood.

The hexosamine pathway and coat complex II promote malignant adaptation to nutrient scarcity.

The glucose-requiring hexosamine biosynthetic pathway (HBP), which produces UDP-N-acetylglucosamine for glycosylation reactions, promotes lung adenocarcinoma (LUAD) progression. However, lung tumor cells often reside in low-nutrient microenvironments, and whether the HBP is involved in the adaptation of LUAD to nutrient stress is unknown. Here, we show that the HBP and the coat complex II (COPII) play a key role in cell survival during glucose shortage.

Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression.

Macrophage ontogeny and functional diversity in cardiometabolic diseases.

Macrophages are the dominant immune cell types in the adipose tissue, the liver or the aortic wall and they were originally believed to mainly derived from monocytes to fuel tissue inflammation in cardiometabolic diseases. However, over the last decade the identification of tissue resident macrophages (trMacs) from embryonic origin in these metabolic tissues has provided a breakthrough in the field forcing to better comprehend macrophage diversity during pathological states. Infiltrated monocyte-derived macrophages (moMacs), similar to trMacs, adapt to the local metabolic environment that eventually shapes their functions.

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy.

Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination-conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment.

Using Genetics To Dissect SARS-CoV-2 Infection.

To uncover the key cellular pathways associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity, Daniloski and coworkers used CRISPR-based whole-genome screening. Their results could propose new or repositioned drugs for the ongoing fight against COVID-19.

Mitochondria orchestrate macrophage effector functions in atherosclerosis.

Macrophages are pivotal in the initiation and development of atherosclerotic cardiovascular diseases. Recent studies have reinforced the importance of mitochondria in metabolic and signaling pathways to maintain macrophage effector functions. In this review, we discuss the past and emerging roles of macrophage mitochondria metabolic diversity in atherosclerosis and the potential avenue as biomarker.

Metabolic Reprogramming of Macrophages in Atherosclerosis: Is It All about Cholesterol?

Hypercholesterolemia contributes to the chronic inflammatory response during the progression of atherosclerosis, in part by favoring cholesterol loading in macrophages and other immune cells. However, macrophages encounter a substantial amount of other lipids and nutrients after ingesting atherogenic lipoprotein particles or clearing apoptotic cells, increasing their metabolic load and impacting their behavior during atherosclerosis plaque progression. This review examines whether and how fatty acids and glucose shape the cellular metabolic reprogramming of macrophages in atherosclerosis to modulate the onset phase of inflammation and the later resolution stage, in which the balance is tipped toward tissue repair.

Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis.

Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C monocytes during NASH, underlying impaired KC self-renewal.

Interplay between Clonal Hematopoiesis of Indeterminate Potential and Metabolism.

Clonal hematopoiesis of indeterminate potential (CHIP), defined as a clone of hematopoietic cells consisting of a single acquired mutation during a lifetime, has recently been discovered to be a major risk factor for atherosclerotic cardiovascular disease (CVD). As such, this phenomenon has sparked interest into the role that these single mutations may play in CVD. Atherosclerotic CVD is a complex disease and we have previously shown that atherosclerosis can be accelerated by metabolic- or autoimmune-related risk factors such as diabetes, obesity, and rheumatoid arthritis.

ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms.

Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro.

Granulopoiesis and Neutrophil Homeostasis: A Metabolic, Daily Balancing Act.

Granulopoiesis is part of the hematopoietic hierarchic architecture, where hematopoietic stem cells give rise to highly proliferative multipotent and lineage-committed granulocytic progenitor cells that differentiate into unipotent neutrophil progenitors. Given their short lifespan, neutrophils are rapidly cleared from circulation through specialized efferocytic macrophages. Together with an intrinsic clock, these processes contribute to circadian fluctuations, preserving self-tolerance and protection against invading pathogens.