Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications

Abstract

Neutrophil extracellular traps (NETs) are network-like structures of chromatin filaments decorated by histones, granules, and cytoplasmic-derived proteins expelled by activated neutrophils under multiple pathogenic conditions. NETs not only capture pathogens in innate immunity but also respond to sterile inflammatory stimuli in atherosclerosis, such as lipoproteins and inflammatory cytokines. Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by the accumulation and transformation of inflammatory cells, and smooth muscle cells in the intimal space. NETs-derived extracellular components possess toxic and proinflammatory properties leading to cellular dysfunction and tissue damage, which may establish a link among lipid metabolism, inflammatory immunity, and atherosclerosis. In this review, we discuss recent advances regarding the role of NETs engaged in the pathogenesis of atherosclerosis, particularly focusing on the interaction with lipids and inflammasomes, crosstalk with smooth muscle cells and inflammatory cells, and the association with aging. We also evaluate the current knowledge on the potential of NETs as biomarkers and therapeutic targets for atherosclerosis and its related diseases in clinical practice.

Keywords: Neutrophil extracellular traps; atherosclerosis; biomarker; inflammation; therapeutic strategies.

Figure 1.

Schematic representation of types and regulatory mechanisms of NETs formation. (a) The classic suicidal NETosis is characterized by nuclear chromatin decondensation, membrane rupture, and cell death. The vital NETs occurred without destroying the cytoplasmic membranes, preserving the phagocytic function of neutrophils. The mitochondrial NETs contain mitochondrial DNA but not nuclear DNA. (b) Extracellular stimulation may result in ROS production through the activation of PKC–MEK–ERK via corresponding membrane receptors. Then, PAD4 is activated, and MPO and NE migrate to the nucleus, leading to chromatin depolymerization and suicidal NETosis. GSDMD and CDK4/6 are also essential regulators by promoting NE translocation to the nucleus during NETosis. The vital NETs occur as a rapid response to LPS and gram-negative bacteria with subsequent elevation of Ca²⁺ and direct activation of PAD4, resulting in the release of nuclear DNA. Following Ca5 stimulation, mitochondrial ROS is produced and the mitochondrial DNA is released instead of nuclear DNA, a process known as mitochondrial NETs.