Background/Purpose:

Patients with RA have an increased risk of developing coronary artery disease (CAD) compared to the general population. The underlying pathological process of CAD is atherosclerosis, which is a chronic inflammatory disease caused by maladaptive inflammatory responses. Macrophages are key players in the progression of atherosclerosis, contributing through proinflammatory effector functions, such as cytokine production. It is currently unknown whether accelerated CAD in RA results from similar or distinct pathomechanisms that underlie non-RA CAD. This study was designed to define and compare proinflammatory macrophages in patients with CAD and RA to clarify their potential contribution to the process of atherosclerosis.

Methods:

Healthy controls, patients with RA who satisfied the ACR classification criteria, and patients with CAD who had a history of at least one myocardial infarction in the absence of co-existent autoimmune disease, were enrolled into this study. Monocytes isolated from peripheral blood mononuclear cells were differentiated into macrophages with M-CSF for 5 days. Macrophages were further differentiated into M1 or M2 with IFN-γ and lipopolysaccharide or IL-4 and IL-13, respectively, for 2 days. RNA was purified from macrophages, and the expressions of 55 genes were measured using quantitative PCR. Cytokine production was quantified by multi-parametric flow cytometry.

Results:

The gene expression signatures of macrophages derived from healthy controls, RA and CAD were significantly different (p<0.01). CAD macrophages were characterized by high production of IL-6 and IL-1β (7.8 and 6.4-fold upregulation compared to controls, p=0.04 and p=0.03, respectively), a phenotype that RA macrophages did not share. CAD macrophages expressed high levels of chemokine receptors including CCR2, CCR5, and CCR7, while RA macrophages expressed similar levels of chemotactic receptors as healthy macrophages. The expression of the transcription factors Kruppel-like factor (KLF)-2 and KLF-4 also distinguished CAD and RA macrophages. KLF-2 and KLF-4 were distinctly low in CAD macrophages (p=0.04 and p= 0.02, respectively), but well maintained in RA macrophages. A characteristic feature of RA macrophages was the high expression of CCL18, a CC chemokine attracting predominantly T lymphocytes. The signature of RA macrophages included the suppression of activation-induced IFN-β, indicating a down-regulation of type 1 IFN-dependent immunity.

Conclusion:

CAD macrophages have a signature of super-inflammatory effector cells, characterized by the loss of negative regulators of inflammation (KLF-2; KLF-4) and the gain of cytokine production capability, releasing high amounts of IL-6 and IL-1β. Because of high expression of chemotactic receptors, they can efficiently navigate through the atherosclerotic plaque to enhance inflammation. In contrast, RA macrophages appear less mobile and are able to amplify inflammation through the CCL18-dependent recruitment of T cells. The data suggest that macrophage-dependent immune responses are fundamentally different in RA and CAD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-profiles-of-proinflammatory-macrophages-in-rheumatoid-arthritis-and-coronary-artery-disease/