Background/Purpose: RA patients have a 2-fold increased risk of developing coronary artery disease (CAD) regardless of traditional risk factors. Atherosclerosis, the underlying process in CAD, is a chronic maladaptive inflammatory response, and macrophages play a critical role in its progression through cytokine and chemokine secretion, production of tissue-injurious enzymes and amplification of adaptive immune responses. Here, we have examined macrophages in RA and CAD, with the goal to identify disease-specific and shared molecular pathways swaying such myeloid cells towards pathogenic inflammation.

Methods: Patients with RA who fulfilled 2010 ACR/EULAR RA Classification Criteria, CAD patients with a history of at least one myocardial infarction (>3 months post event), and healthy controls were enrolled. Monocytes isolated from peripheral blood were differentiated into macrophages with macrophage colony stimulating factor. To recapitulate an inflammatory tissue environment, macrophages were stimulated with IFN-γ and lipopolysaccharide. Gene expression profiles were analyzed by quantitative RT-PCR. Intracellular cytokines were measured by flow cytometry. Intracellular reactive oxygen species (ROS) were quantified using CellROX. The oxidant superoxide was scavenged using the superoxide dismutase mimetic, Tempol.

Results: Compared to healthy macrophages, RA and CAD macrophages shared the enhanced expression of the oxidative stress response gene, NAD(P)H:quinone oxidoreductase 1 (NQO1). Measurements with redox-sensitive probes confirmed an oversupply of reactive oxidant species. Also, RA and CAD macrophages were programmed to produce higher levels of the chemokine CCL18, which promotes T cell recruitment and is highly expressed in the atherosclerotic plaque. Scavenging of ROS with Tempol suppressed CCL18 production, implicating oxidant species in regulating the chemokine secretion profile. Depriving macrophages of glucose had profound implications on both ROS production and the gene expression pattern. Specifically, reducing glycolytic flux by treatment with 2-deoxy-glucose restored the expression of the negative regulators Krüppel-like factor (KLF)2 and KLF4, which inhibit inflammatory effector functions.

Conclusion: Enhanced glucose metabolism acts as an upstream regulator of inflammatory macrophage functions. ROS, produced in excess by glucose-addicted macrophages, influence the chemokine production pattern, specifically CCL18, a predominant chemokine in atherosclerotic plaque. Patients with RA and CAD share common features in macrophage differentiation towards hyperinflammtory effector cells. Such macrophages may contribute to the acceleration of CAD in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-oxidant-signaling-in-inflammatory-macrophages-in-rheumatoid-arthritis-ra-and-in-coronary-artery-disease-cad/