Research Advances on the Role of Immune Cells and Inflammatory Mediators in Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disease driven by dynamic interactions between lipid metabolism and immune responses. Its initiation and progression are co-regulated by innate and adaptive immunity. Innate immune cells are central to early plaque development. Neutrophils release pro-inflammatory mediators, including myeloperoxidase (MPO) and neutrophil extracellular traps (NETs), which contribute to endothelial dysfunction and tissue injury. Circulating monocytes infiltrate the arterial intima and differentiate into macrophages. These macrophages can polarize into distinct phenotypes, typically categorized as pro-inflammatory M1 or anti-inflammatory M2; an imbalance between these states exacerbates plaque inflammation. A pivotal early event is the uptake of modified lipoproteins—such as oxidized low-density lipoprotein (oxLDL)—via scavenger receptors (e.g., SR-A1 and CD36), leading to the formation of lipid-laden foam cells, a hallmark of early lesions. Adaptive immune responses also shape disease progression and plaque stability. Among CD4+ T helper subsets, Th1 cells promote atherosclerosis by secreting interferon-γ (IFN-γ), whereas Th17 cells and their signature cytokine interleukin-17 (IL-17) are often associated with disease amplification. In contrast, regulatory T cells (Tregs) exert atheroprotective effects by suppressing immune activation and producing anti-inflammatory cytokines such as interleukin-10 (IL-10). B cells also contribute: B1 cells are generally protective, in part through natural IgM production, whereas B2 cells may be pro-atherogenic. Key inflammatory pathways sustain the chronic inflammatory milieu within plaques. The NLRP3 inflammasome, activated by damage-associated molecular patterns (DAMPs) such as cholesterol crystals, induces caspase-1 activation, which cleaves pro–IL-1β and pro–IL-18 into their bioactive forms. Cytokines including IL-1β and IL-6 are major drivers of inflammation; IL-1β upregulates endothelial adhesion molecules, whereas IL-6 promotes the hepatic production of acute-phase reactants. The association between systemic inflammatory diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis) and accelerated atherosclerosis further underscores the importance of shared immune pathways. This review synthesizes these interactions to provide a framework for understanding atherosclerosis pathogenesis.