Defective macrophage efferocytosis in advanced atherosclerotic plaque and mitochondrial therapy

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease primarily affecting large and medium-sized arterial vessels, characterized by lipoprotein disorders, intimal thickening, smooth muscle cell proliferation, and the formation of vulnerable plaques. Macrophages (MΦs) play a vital role in the inflammatory response throughout all stages of atherosclerotic development and are considered significant therapeutic targets. In early lesions, macrophage efferocytosis rapidly eliminates harmful cells. However, impaired efferocytosis in advanced plaques perpetuates the inflammatory microenvironment of AS. Defective efferocytosis has emerged as a key factor in atherosclerotic pathogenesis and the progression to severe cardiovascular disease. Herein, this review probes into investigate the potential mechanisms at the cellular, molecular, and organelle levels underlying defective macrophage efferocytosis in advanced lesion plaques. In the inflammatory microenvironments of AS with interactions among diverse inflammatory immune cells, impaired macrophage efferocytosis is strongly linked to multiple factors, such as a lower absolute number of phagocytes, the aberrant expression of crucial molecules, and impaired mitochondrial energy provision in phagocytes. Thus, focusing on molecular targets to enhance macrophage efferocytosis or targeting mitochondrial therapy to restore macrophage metabolism homeostasis has emerged as a potential strategy to mitigate the progression of advanced atherosclerotic plaque, providing various treatment options.