Atherosclerosis is a chronic multifactorial disease of the arterial wall characterized by inflammation, oxidative stress, and immune\nsystem activation. Evidence exists on a pathogenic role of oxidized red blood cells (RBCs) accumulated in the lesion after intraplaque\nhemorrhage. This review reports current knowledge on the impact of oxidative stress in RBC modifications with the surface\nappearance of senescent signals characterized by reduced expression of CD47 and glycophorin A and higher externalization\nof phosphatidylserine. The review summarizes findings indicating that oxidized, senescent, or stored RBCs, due to surface\nantigen modification and release of prooxidant and proinflammatory molecules, exert an impaired modulatory activity on innate\nand adaptive immune cells and how this activity contributes to atherosclerotic disease. In particular RBCs from patients with\natherosclerosis, unlike those from healthy subjects, fail to control lipopolysaccharide-induced DC maturation and T lymphocyte\napoptosis. Stored RBCs, accompanied by shedding of extracellular vesicles, stimulate peripheral blood mononuclear cells to release\nproinflammatory cytokines, augment mitogen-driven T cell proliferation, and polarize macrophages toward the proinflammatory\nM1 activation pathway. Collectively, literature data suggest that the crosstalk between RBCs with immune cells represents a novel\nmechanism by which oxidative stress can contribute to atherosclerotic disease progression and may be exploited for therapeutic\ninterventions.
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