Phenotype and Response to PAMPs of Human Monocyte-Derived Foam Cells Obtained by Long-Term Culture in the Presence of oxLDLs

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.

microRNA-155 Is Decreased During Atherosclerosis Regression and Is Increased in Urinary Extracellular Vesicles During Atherosclerosis Progression

“…Notably, miR-155 regulates multiple cell death pathways, as macrophage derived miR-155 containing exosomes enhanced pyroptosis in cardiomyocytes through the direct targeting of FoxO3a (63). Human monocyte derived foam cells, obtained after prolonged exposure to oxidized LDL [a known inducer of miR-155 expression (46,64)], respond to inflammasome activation preferentially with pyroptosis combined with other types of necrotic death (65). Thus, it could be speculated that switching between cell death pathways is an effector mechanism of miR-155 as these pathways have the capacity to regulate the immunogenic cell death burden which can contribute to atherosclerosis development.…”

Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms

“…It also promotes necrotic core formation in advanced atherosclerosis. In vitro study shows that low-concentration ox-LDL treatment induces pyroptosis in human monocyte-derived foam cells ( 107 , 108 ). Absent in melanoma 2 (AIM2)-dependent macrophage pyroptosis exacerbates atherosclerosis as well.…”

Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway

“…Actually, the high concentration of TNF-α released after treatment with CitH3 and H3 can also induced other lytic cell death like necroptosis ( 53 ). Interestingly, a recent study showed that prolonged exposure of myeloid cells to DAMPs like oxLDLs can induce cell to switch between cell death pathways ( 54 ). CitH3 and H3 may also activate different cell death pathways simultaneously or undergo a transition between different cell death pathways.…”