Targeting immune cell recruitment in atherosclerosis

Atherosclerosis is the primary underlying cause of myocardial infarction and stroke. Atherosclerotic cardiovascular disease is characterized by a chronic inflammatory reaction in medium-to-large-sized arteries, with its onset and perpetuation driven by leukocytes infiltrating the subendothelial space. Activation of endothelial cells triggered by hyperlipidaemia and lipoprotein retention in the arterial intima initiates the accumulation of pro-inflammatory leukocytes in the arterial wall, fostering the progression of atherosclerosis. This inflammatory response is coordinated by an array of soluble mediators, namely cytokines and chemokines, that amplify inflammation both locally and systemically and are complemented by tissue-specific molecules that regulate the homing, adhesion and transmigration of leukocytes. Despite abundant evidence from mouse models, only a few therapies targeting leukocytes in atherosclerosis have been assessed in humans. The major challenges for the clinical translation of these therapies include the lack of tissue specificity and insufficient selectivity of inhibition strategies. In this Review, we discuss the latest research on receptor-ligand pairs and interactors that regulate leukocyte influx into the inflamed artery wall, primarily focusing on studies that used pharmacological interventions. We also discuss mechanisms that promote the resolution of inflammation and highlight how major findings from these research areas hold promise as potential therapeutic strategies for atherosclerotic cardiovascular disease. In this Review, the authors discuss the receptors, ligands and interactors that regulate immune cell recruitment in atherosclerosis, describe mechanisms that promote the resolution of inflammation in atherosclerotic lesions, and highlight potential strategies to target these pathways for the treatment of atherosclerotic cardiovascular disease. Preclinical studies have demonstrated that targeting of chemokine-chemokine receptor pathways is a promising therapeutic approach, although additional clinical studies are required to validate the potential of these approaches.Formation of heterodimers of chemokines and chemokine receptors provides an additional layer of complexity in the chemokine-receptor network, which has so far been underestimated and might offer refined therapeutic potential in the future.Circadian rhythmicity of leukocyte migration patterns is an important mechanism that remains undervalued and should be considered when devising clinical interventions to target leukocyte recruitment.Fostering the resolution of inflammation by supplementation with polyunsaturated fatty acids has shown benefits in preclinical and clinical studies, although targeted delivery approaches should be developed to improve efficacy.Despite promising findings from preclinical studies, IL-10 supplementation and transfer of regulatory T cells have not yet been assessed in the clinical setting and thus warrant future study.