Oxidized low‐density lipoproteins impair the pro‐atherosclerotic effect of granulocyte‐macrophage‐colony‐stimulating factor‐producing T helper cells on macrophages

Abstract

AbstractT cells contribute to the pathogenesis of atherosclerosis. However, the presence and function of granulocyte‐macrophage‐colony‐stimulating factor (GM‐CSF)‐producing T helper (ThGM) cells in atherosclerosis development is unknown. This study aims to characterize the phenotype and function of ThGM cells in experimental atherosclerosis. Atherosclerosis was induced by feeding apolipoprotein E knockout (ApoE−/−) mice with a high‐fat diet. Aortic ThGM cells were detected and sorted by flow cytometry. The effect of oxidized low‐density lipoprotein (oxLDL) on ThGM cells and the impact of ThGM cells on macrophages were evaluated by flow cytometry, quantitative RT‐PCR, oxLDL binding/uptake assay, immunoblotting and foam cell formation assay. We found that GM‐CSF+IFN‐γ− ThGM cells existed in atherosclerotic aortas. Live ThGM cells were enriched in aortic CD4+CCR6−CCR8−CXCR3−CCR10+ T cells. Aortic ThGM cells triggered the expression of interleukin‐1β (IL‐1β), tumour necrosis factor (TNF), interleukin‐6 (IL‐6) and C‐C motif chemokine ligand 2 (CCL2) in macrophages. Besides, aortic ThGM cells expressed higher CD69 than other T cells and bound to oxLDL. oxLDL suppressed the cytokine expression in ThGM cells probably via inhibiting the signal transducer and activator of transcription 5 (STAT5) signalling. Furthermore, oxLDL alleviated the effect of ThGM cells on inducing macrophages to produce pro‐inflammatory cytokines and generate foam cells. The nuclear receptor subfamily 4 group A (NR4A) members NR4A1 and NR4A2 were involved in the suppressive effect of oxLDL on ThGM cells. Collectively, oxLDL suppressed the supportive effect of ThGM cells on pro‐atherosclerotic macrophages.