Shirai et al. show that the glycolytic enzyme PKM2 serves as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation in macrophages from patients with atherosclerotic coronary artery disease.

No abstract

Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.

BACKGROUND. In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling. METHODS. To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA). RESULTS. Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1β and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1β and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokine hi cytokine hi PD-L1 hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function. CONCLUSIONS. We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment.

No abstract

The locus, Aph

No abstract

Background: Autoimmune disease is an independent risk factor for accelerated coronary artery disease (CAD). Patients with rheumatoid arthritis (RA) have a 2-fold increased risk for CAD, comparable to the impact of diabetes mellitus. Abnormalities in the immune system contribute to both RA and CAD pathogenesis and defining these might elucidate disease mechanisms. We studied inflammatory macrophages in RA and CAD to identify shared and disease-specific molecular pathways. Methods: Patients with CAD and a history of myocardial infarction, patients with RA who satisfied the 2010 RA Classification Criteria and age-matched controls were enrolled. Monocytes isolated from peripheral blood were differentiated into macrophages and further polarized into M1 or M2 with IFNγ and lipopolysaccharide or IL-4 and IL-13, respectively. The expression of 55 genes was measured by quantitative PCR. Intracellular reactive oxygen species (ROS) were quantified using CellROX and the oxidant superoxide was scavenged using the SOD mimetic Tempol. Results: Both CAD and RA macrophages exhibited a gene expression signature of excess inflammatory activity when compared to controls. Besides the upregulation of cytokine genes, the hyper-inflammatory signature included the loss of the inflammatory suppressors Krüppel-like factor (KLF)-2 and KLF-4, and the gain of the chemokine CCL18 and the oxidative stress response gene, NAD(P)H:quinone oxidoreductase 1 (NQO1). Quantification of intracellular ROS confirmed increased oxidative stress in the patient-derived macrophages. To examine whether superoxide affects production of CCL18, cells were treated with Tempol. ROS depletion normalized the excess production of CCL18. Conclusion: Pro-inflammatory macrophages in RA and CAD share molecular abnormalities characterized by excessive cytokines and chemokine production, the loss of negative regulators and the gain of oxidative stress responses. Unbalanced ROS production is upstream of abnormal chemokine production and correcting redox balance in macrophages may be helpful in suppressing the hyper-inflammatory phenotype of these cells in CAD and in the CAD-prone autoimmune disease RA.