Quercetin alleviates atherosclerosis associated with reduced lysophosphatidylcholine-induced macrophage extracellular traps formation and modulation of the JNK/Sp1/PAD4 pathway

Macrophage extracellular traps (METs) are reticular structures released by macrophages that contribute to inflammatory responses. Excessive formation and accumulation of METs have been implicated in the progression of atherosclerosis (AS). While lysophosphatidylcholine (LPC), a major component of oxidized low-density lipoprotein, is a recognized risk factor for AS, prior studies have largely emphasized the pathological contribution of neutrophil extracellular traps during atherogenesis. In contrast, macrophages represent a dominant cellular component of atherosclerotic plaques, yet the role of METs in LPC-associated atherosclerotic progression remains poorly understood. The effects of quercetin on METs in atherosclerosis have also not been fully established. In this study, we provide evidence that METs are involved in LPC-associated atherosclerotic progression. Increased METs formation was observed in plaque-rich aortic tissues of HFD-fed mice, whereas quercetin supplementation reduced METs markers and attenuated atherosclerotic lesions, accompanied by decreased JNK phosphorylation and reduced specificity protein 1 (Sp1) and PAD4 expression. In vitro, LPC induced METs formation in RAW264.7 cells and upregulated JNK/Sp1/PAD4-associated proteins. Pharmacological inhibition of JNK or Sp1 suppressed LPC-induced METs formation, supporting a role for this signaling cascade in METs generation. Notably, this study is the first to identify the JNK/Sp1/PAD4 axis as a potential regulatory pathway mediating LPC-induced METs formation in macrophages. Quercetin attenuated LPC-induced METs formation, and this effect was reversed by a JNK Activator. Collectively, these findings suggest that quercetin alleviates AS and that suppression of LPC-induced METs formation via modulation of the JNK/Sp1/PAD4 pathway may represent 1 potential mechanism underlying its protective effects.