Abstract
Neutrophil extracellular traps (NETs) are web-like structures, which are released upon neutrophil activation. It has previously been demonstrated that NETs are present in atherosclerotic lesions of both humans and animal models thus playing a decisive role in atherosclerosis. Besides, macrophages have a crucial role in disease progression, whereby classically activated M1 macrophages sustain inflammation and alternatively activated M2 macrophages display anti-inflammatory effects. Although NETs and macrophages were found to colocalize in atherosclerotic lesions, the impact of NETs on macrophage function is not fully understood. In the present study, we aimed to investigate the effect of NETs on human and murine macrophages in respect to the expression of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and uptake of oxidized LDL (oxLDL) in vitro. Human THP-1 and murine bone marrow-derived macrophages were cultured under M1 (LPS + IFN-γ)- and M2a (IL-4)-polarizing culture conditions and treated with NETs. To mimic intraplaque regions, cells were additionally cultured under hypoxic conditions. NETs significantly increased the expression of IL-1β, TNF-α and IL-6 in THP-M1 macrophages under normoxia but suppressed their expression in murine M1 macrophages under hypoxic conditions. Notably, NETs increased the number of oxLDL-positive M1 and M2 human and murine macrophages under normoxia, but did not influence formation of murine foam cells under hypoxia. However, oxLDL uptake did not strongly correlate with the expression of the LDL receptor CD36. Besides, upregulated MMP-9 expression and secretion by macrophages was detected in the presence of NETs. Again, hypoxic culture conditions dampened NETs effects. These results suggest that NETs may favor foam cell formation and plaque vulnerability, but exert opposite effects in respect to the inflammatory response of human and murine M1 macrophages. Moreover, effects of NETs on macrophages’ phenotype are altered under hypoxia.
Highlights
Atherosclerosis is recognized as the primary pathophysiology of cardiovascular disease and the leading cause of morbidity and mortality worldwide
Neutrophil extracellular traps and macrophages is a hallmark of atherosclerosis and many different cell types, including granulocytes, monocytes/ macrophages, dendritic cells, T-cells, B-cells and mast cells contribute to disease progression [1]
In the present in vitro study, we have compared the impact of Neutrophil extracellular traps (NETs) on human and murine macrophages in respect to the expression of cytokines and matrix metalloproteinases (MMPs) as well as foam cell formation
Summary
Atherosclerosis is recognized as the primary pathophysiology of cardiovascular disease and the leading cause of morbidity and mortality worldwide. Neutrophil extracellular traps and macrophages is a hallmark of atherosclerosis and many different cell types, including granulocytes, monocytes/ macrophages, dendritic cells, T-cells, B-cells and mast cells contribute to disease progression [1]. The initiating step in the development of atherosclerosis is the accumulation of low-density lipoproteins (LDL) that become sequestrated in the subendothelial space and trigger inflammatory responses inducing monocyte attraction. These monocytes subsequently differentiate into macrophages that scavenge oxidized LDL resulting in the formation of the foam cells. Foam cell buildup contributes to plaque lipid storage and sustained plaque growth [2]
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