Background/Purpose: Macrophages are key effector cells in the vessel wall inflammation of the atherosclerotic plaque as well as in the intramural infiltrates of giant cell arteritis (GCA). The histomorphology of both diseases is distinct; GCA macrophages are arranged in granulomatous lesions and form giant cells, whereas plaque-residing macrophages facilitate lipid uptake and participate in a fibro-inflammatory reparative process. Whether the profile of inflammatory macrophage functions is comparable in both conditions and which signaling pathways drive macrophage activation in the vessel wall lesions is insufficiently understood.

Methods: Tissue-residing macrophages were analyzed in biopsies from atherosclerotic plaques and from GCA-affected temporal arteries. Monocyte-derived macrophages were generated from peripheral blood CD14+ precursor cells by differentiating the cells with M-CSF over a 5-day culture. Macrophages were stimulated with 100 U/ml IFN-γ and 100 ng/ml LPS. Patients were enrolled if they had (a) at least one documented myocardial infarct or (b) a temporal artery biopsy positive for GCA. Tissue transcriptomes and gene expression panels from macrophages were established by RT-PCR. Protein expression was examined by flow cytometry and by immunohistochemical staining of tissue sections.

Results: In macrophages from patients with CAD glucose transporters and enzymes of the glycolytic pathway were strongly upregulated (Glut1, HK2, GAPDH, PKM1, PGM1, HIF1α, and c-myc). Glucose and its breakdown product pyruvate directly controlled the production of inflammatory cytokines (IL-1b, IL-6) and regulated the expression of co-stimulatory (CD80, CD86) and co-inhibitory ligands (PD-L1). Most plaque-residing macrophages were PD-L1^hi expressors. In contrast, the glycolytic machinery was not upregulated in GCA macrophages. Profiling for chemokines and cytokines revealed high expression of CXCL9, 10 and 11 in GCA macrophages, but the inflammatory cytokines IL-1, IL-6 and TNF were indistinguishable in GCA patients versus normal controls. Opposite to CAD macrophages, GCA macrophages were characterized by low expression of the co-inhibitory ligand PD-L1. Tissue-residing cells in temporal artery lesions also had the PD-L1^low phenotype.

Conclusion: Signaling pathways driving the activation of macrophages in the atherosclerotic plaque and in GCA lesions are fundamentally different. CAD macrophages are characterized by a metabolic defect, over-utilize glucose and are functionally a hybrid between excess cytokine release and high expression of PD-L1. GCA macrophages are biased towards chemokine production. The low expression of the immuno-inhibitory ligand PD-L1 enables them to strongly promote T cell effector functions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparative-analysis-of-the-macrophage-glycolytic-machinery-in-giant-cell-arteritis-gca-and-in-coronary-artery-disease-cad/