Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice.

Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice.

Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice.

Objective: The intersection between immunology and metabolism contributes to the pathogenesis of obesity-associated metabolic diseases as well as molecular control of inflammatory responses. The metabolite itaconate and the cell-permeable derivatives have robust anti-inflammatory effects; therefore, it is hypothesized that cis-aconitate decarboxylase (Acod1)-produced itaconate has a protective, anti-inflammatory effect during diet-induced obesity and metabolic disease.

Methods: Wild-type and Acod1 mice were subjected to diet-induced obesity.

Aconitate decarboxylase 1 suppresses cerebral ischemia-reperfusion injury in mice.

Immunometabolic changes have been shown to be a key factor in determining the immune cell response in disease models. The immunometabolite, itaconate, is produced by aconitate decarboxylase 1 (Acod1) and has been shown to inhibit inflammatory signaling in macrophages. In this study, we explore the role of Acod1 and itaconate in cerebral ischemia/reperfusion injury.

High-fat and high-sodium diet induces metabolic dysfunction in the absence of obesity.

Objective: Excess dietary fat and sodium (NaCl) are both associated with obesity and metabolic dysfunction. In mice, high NaCl has been shown to block high-fat (HF) diet-induced weight gain. Here, the impact of an HF/NaCl diet on metabolic function in the absence of obesity was investigated.

Inactivation of Interleukin-4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt-Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling.

Background Hypertension-induced cardiovascular remodeling is characterized by chronic low-grade inflammation. Interleukin-4 receptor α (IL-4Rα) signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s) is unclear. Here, we investigated the role of myeloid-specific IL-4Rα signaling in cardiovascular remodeling induced by angiotensin II and high salt.

Myeloid interleukin-4 receptor α is essential in postmyocardial infarction healing by regulating inflammation and fibrotic remodeling.

Interleukin-4 receptor α (IL4Rα) signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4Rα signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4Rα signaling in cardiac remodeling post-MI.

Neutrophils Restrict Tumor-Associated Microbiota to Reduce Growth and Invasion of Colon Tumors in Mice.

Background & Aims: Neutrophils are among the most prevalent immune cells in the microenvironment of colon tumors; they are believed to promote growth of colon tumors, and their numbers correlate with outcomes of patients with colon cancer. Trials of inhibitors of neutrophil trafficking are underway in patients with cancer, but it is not clear how neutrophils contribute to colon tumorigenesis.

Methods: Colitis-associated colon cancer was induced in mice with conditional deletion of neutrophils (LysMCre;Mcl1) and wild-type littermates (LysMCre;Mcl1, control mice) by administration of azoxythmethane and/or dextran sulfate sodium.

Genetic neutrophil deficiency ameliorates cerebral ischemia-reperfusion injury.

Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Myeloid Mcl1 knockout mice were subjected to transient middle cerebral artery occlusion and infarct size was assessed by MRI after 24h reperfusion.

Depletion of macrophages in CD11b diphtheria toxin receptor mice induces brain inflammation and enhances inflammatory signaling during traumatic brain injury.

Immune cells have important roles during disease and are known to contribute to secondary, inflammation-induced injury after traumatic brain injury. To delineate the functional role of macrophages during traumatic brain injury, we depleted macrophages using transgenic CD11b-DTR mice and subjected them to controlled cortical impact. We found that macrophage depletion had no effect on lesion size assessed by T2-weighted MRI scans 28 days after injury.

Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation.

Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex.

Background: Mineralocorticoid receptor (MR) antagonists have protective effects in the brain during experimental ischemic stroke, and we have previously demonstrated a key role for myeloid MR during stroke pathogenesis. In this study, we explore both model- and sex-specific actions of myeloid MR during ischemic stroke.

Methods And Results: The MR antagonist eplerenone significantly reduced the infarct size in male (control, 99.

Smooth muscle protein 22 alpha-Cre is expressed in myeloid cells in mice.

Background: Experiments using Cre recombinase to study smooth muscle specific functions rely on strict specificity of Cre transgene expression. Therefore, accurate determination of Cre activity is critical to the interpretation of experiments using smooth muscle specific Cre.

Methods And Results: Two lines of smooth muscle protein 22 α-Cre (SM22α-Cre) mice were bred to floxed mice in order to define Cre transgene expression.

Nuclear receptor control of opposing macrophage phenotypes in cardiovascular disease.

Macrophages have important physiological roles and display a high degree of heterogeneous phenotypes in response to a variety of stimuli. In particular, the spectrum of alternatively activated macrophages has been a focus because many lines of evidence indicate a cardioprotective role for this macrophage phenotype. This phenotype is controlled in part by opposing nuclear transcription factors including the PPARs that stimulate alternative activation and the recently recognized role of the mineralocorticoid receptor in stimulating classically activated macrophages.

Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.

Background And Purpose: mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice.

Methods: myeloid-specific MR knockout mice were subjected to transient (90 minutes) middle cerebral artery occlusion followed by 24 hours reperfusion (n=5 to 7 per group).

Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.

Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflammatory cytokines.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer.

Quantitative determination of free glycerol and myo-inositol from plasma and tissue by high-performance liquid chromatography.

A high-performance liquid chromatographic method that accurately measures glycerol and myo-inositol from plasma and tissue is described. The method incorporates a pre-column derivatization reaction using aqueous extracts with benzoyl chloride as a modifying agent. The benzoylated derivatives are isolated by HPLC using reversed-phase gradient chromatography and quantified via absorbance detection at 231 nm.