Targeting the TLR4/PAD4-mediated formation of macrophage extracellular traps by curcumin attenuates plaque destabilization in ulcerative colitis-associated atherosclerosis

Acute ulcerative colitis elevates the risk of plaque rupture in patients with atherosclerosis, potentially triggering acute cardiovascular events. Clinical treatment strategies capable of simultaneously alleviating colitis and stabilizing atherosclerotic plaques are still lacking. Extracellular traps have been observed within atherosclerotic plaques in patients with myocardial ischemia. Given the crucial role of macrophages in the formation and progression of plaques, whether macrophage extracellular traps (METs) significantly contribute to the stability of atherosclerotic (AS) plaques during acute inflammation remains unclear. Curcumin exhibits lipid-lowering and anti inflammatory properties; however, its potential to stabilize AS plaques under inflammatory conditions and its specific effects on METs have yet to be elucidated. This study aims to investigate whether curcumin can stabilize atherosclerotic plaques in an acute inflammatory state and to explore its underlying mechanisms. Curcumin treatment significantly reduced the necrotic core of unstable plaques and increased Collagen content in atherosclerotic mice with ulcerative colitis, thereby markedly stabilizing the plaques. Curcumin inhibited TLR4 activity and the production of inflammatory cytokines, including TNF-α, IL-6, IL-1β, S100A8, and S100A9. It also suppressed PAD4 activation, leading to decreased formation of macrophage extracellular traps (METs) and downregulated expression of collagen-degrading matrix metalloproteinase 9 (MMP9). Our findings suggested that curcumin enhances the stability of atherosclerotic plaques under acute inflammatory conditions by attenuating METs formation and reducing inflammation through suppression of TLR4/PAD4, shedding new light on its anti-atherosclerotic mechanism and providing a novel treatment for inflammatory comorbidity.