Abstract
Cholesterol-laden, foam macrophages constitute the most characteristic component of human atherosclerotic plaques. Persistent uptake of oxLDLs results in accumulation of lipid bodies inside the cells and determines their phenotype and subsequent functions. In this work, we describe the phenotype of human monocyte-derived foam cells obtained by differentiation in the constant presence of oxLDLs for 30 days (prolonged-hMDFCs). Although neither the total cellular nor the cell surface expression of Toll-like receptors (TLR) was regulated by oxLDLs, the prolonged-hMDFCs changed dramatically their responsiveness to TLR ligands and inactivated bacteria. Using multiplex technology, we observed an acute decline in cytokine and chemokine production after surface and endosomal TLR stimulation with the exception of TLR2/6 triggering with agonists Pam2CSK4 and MALP-2. We also noted significant reduction of some surface receptors which can have accessory function in recognition of particulate antigens (CD47, CD81, and CD11b). In contrast, the prolonged-hMDFCs responded to inflammasome activation by LPS/nigericin with extensive, necrotic type cell death, which was partially independent of caspase-1. This pyroptosis-like cell death was aggravated by necrostatin-1 and rapamycin. These findings identify a potential contribution of mature foam cells to inflammatory status by increasing the immunogenic cell death burden. The observed cross-talk between foam cell death pathways may lead to recognition of a potential new marker for atherosclerosis disease severity. Overall, our study demonstrates that, in contrast to other cellular models of foam cells, the prolonged-hMDFCs acquire a functional phenotype which may help understanding the role of foam cells in the pathogenesis of atherosclerosis.
Highlights
Atherosclerosis is clinically manifested as cardiovascular diseases, which are the number 1 cause of death globally [1]
Comparative flow cytometry analysis of cell-surface expression of Toll-like receptors (TLR) demonstrated no significant differences between Human Monocyte-Derived Macrophages (hMDMs) and human monocyte-derived foam cells (hMDFCs) cultured for prolonged time (Figures 2B,D and Supplementary Table 1). hMDFCs expressed significantly less CD47, CD81, and CD11b, while only a slight decrease was observed for CD14, CD16, and CD36 (Figures 2C,E,F, Supplementary Tables 1, 2)
The long-term oxidatively modified low density lipoproteins (oxLDLs) loading was not a proinflammatory event but rather it reduced the inflammatory response when hMDFCs were stimulated with LPS, Poly (I:C), and Pam3CSK4—ligands of TLR4, TLR3, and TLR2/1, respectively (Figure 4)
Summary
Atherosclerosis is clinically manifested as cardiovascular diseases, which are the number 1 cause of death globally [1]. Clinically relevant lesions become evident in middle-aged adults, it has been demonstrated that fat accumulation (known as fatty streaks) begins in early childhood [2]. The latency period is long, and clinical manifestations become evident in middle-aged and older adults [3]. One of the key processes responsible for atherosclerosis is the accumulation of monocyte/macrophage lineage cells within the lipid-rich subendothelial space of the affected artery [4]. Consecutive formation of foam macrophages is a pivotal process in the development of the atherosclerotic plaque [5]. Foam cell formation is a beneficial process in the early atherosclerotic lesion, in advanced lesions the foam cells die and release their contents (damage-associated molecular patterns, DAMPs) to the extracellular space [7, 8]
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