Ira AND tabas

Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA-PKcs-mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression...

Nanotechnology could improve our understanding of the pathophysiology of atherosclerosis and contribute to the development of novel diagnostic and therapeutic strategies to further reduce the risk of cardiovascular disease. Macrophages have key roles in atherosclerosis progression and, therefore, macrophage-associated pathological processes are important targets for both diagnostic imaging and novel therapies for atherosclerosis. In this Review, we highlight efforts in the past two decades to develop imaging techniques and to therapeutically manipulate macrophages in atherosclerotic plaques with the use of rationally designed nanoparticles...

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)-induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 ( JAG1 ) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signaling in pericentral hepatocytes...

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice...

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4...

Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis...

Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. Although the role of MerTK in cardioprotection is well characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically relevant models of myocardial ischemia/reperfusion infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a maladaptive role for myeloid AXL during IRI in the heart...

AIMS: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy. METHODS AND RESULTS: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE...

OBJECTIVE: ODC (ornithine decarboxylase)-dependent putrescine synthesis promotes the successive clearance of apoptotic cells (ACs) by macrophages, contributing to inflammation resolution. However, it remains unknown whether ODC is required for other arms of the resolution program. Approach and Results: RNA sequencing of ODC-deficient macrophages exposed to ACs showed increases in mRNAs associated with heightened inflammation and decreases in mRNAs related to resolution and repair compared with WT (wild type) macrophages...

No abstract text is available yet for this article.

With the rapid expansion of the obesity epidemic, nonalcoholic fatty liver disease is now the most common chronic liver disease, with almost 25% global prevalence. Nonalcoholic fatty liver disease ranges in severity from simple steatosis, a benign 'pre-disease' state, to the liver injury and inflammation that characterize nonalcoholic steatohepatitis (NASH), which in turn predisposes individuals to liver fibrosis. Fibrosis is the major determinant of clinical outcomes in patients with NASH and is associated with increased risks of cirrhosis and hepatocellular carcinoma...

Atherosclerotic lesional macrophages express molecules that promote plaque progression, but lack of mechanisms to therapeutically target these molecules represents a major gap in translational cardiovascular research. Here, we tested the efficacy of a small interfering RNA (siRNA) nanoparticle (NP) platform targeting a plaque-destabilizing macrophage molecule-Ca2+ /calmodulin-dependent protein kinase γ (CaMKIIγ). CaMKIIγ becomes activated in advanced human and mouse plaque macrophages and drives plaque necrosis by suppressing the expression of the efferocytosis receptor MerTK...

Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression...

Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes, and tight glycemic control fails to reduce the risk of developing CVD. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor γ (PPARγ) agonists, are potent insulin sensitizers with antiatherogenic properties, but their clinical use is limited by side effects. PPARγ deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples the adverse effects of TZDs from insulin sensitization...

Macrophage immunometabolism, the changes in intracellular metabolic pathways that alter the function of these highly plastic cells, has been the subject of intense interest in the past few years, in part because macrophage immunometabolism plays important roles in atherosclerosis and other inflammatory diseases. In this review article, part of the Compendium on Atherosclerosis , we introduce the concepts of (1) intracellular immunometabolism-the canonical pathways of intrinsic cell activation leading to changes in intracellular metabolism, which in turn alter cellular function; and (2) intercellular immunometabolism-conditions in which intermediates of cellular metabolism are transferred from one cell to another, thereby altering the function of the recipient cell...

Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation...

Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk...

Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here, we show that the process is optimized by linking the metabolism of engulfed cargo from initial efferocytic events to subsequent rounds. We found that continual efferocytosis is enhanced by the metabolism of AC-derived arginine and ornithine to putrescine by macrophage arginase 1 (Arg1) and ornithine decarboxylase (ODC). Putrescine augments HuR-mediated stabilization of the mRNA encoding the GTP-exchange factor Dbl, which activates actin-regulating Rac1 to facilitate subsequent rounds of AC internalization...

Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data...

The clearance of apoptotic cells by professional and non-professional phagocytes - a process termed 'efferocytosis' - is essential for the maintenance of tissue homeostasis. Accordingly, defective efferocytosis underlies a growing list of chronic inflammatory diseases. Although much has been learnt about the mechanisms of apoptotic cell recognition and uptake, several key areas remain incompletely understood. This Review focuses on new discoveries related to how phagocytes process the metabolic cargo they receive during apoptotic cell uptake; the links between efferocytosis and the resolution of inflammation in health and disease; and the roles of efferocytosis in host defence...