In vivo investigation of non-classical monocyte patrolling mechanism

La Jolla Institute For Immunology, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): Blood monocytes circulate in the periphery as predominantly two subsets: classical and non- classical, or patrolling, monocytes. It has been shown that classical monocytes contribute early on to the process of atherosclerosis by adhering to the vasculature and migrating to the inner layers of the vessel wall, primarily using selectins and integrins, to eventually become foam cells, leading to a chronic inflammatory state within the vascular layers. The endothelial layer of the blood vessel also becomes activated, releasing pro-inflammatory cytokines and chemokines as well as upregulating integrin ligands such as VCAM-1. Non-classical monocytes have been shown to migrate to plaque sites, although they are less frequent than classical monocytes inside the plaque and upregulate different cell surface markers. During steady state, these non-classical monocytes will spend prolonged times crawling non-directionally along the endothelium to survey the vasculature, although more frequently found in smaller vessels than larger vessels. We have found that during atherogenesis, by feeding mice a western diet that is high in fat and cholesterol, there is a significant increase in the patrolling activity of non-classical monocytes. Previous work in our lab has suggested that these monocytes are atheroprotective, as their absence leads to increases in plaque size and inflammatory monocyte numbers. The function of these non-classical monocytes in atherosclerosis, and the exact mechanism of patrolling, is still unclear, but by studying how non-classical monocytes are activated by this disease, we may be able to elucidate a novel target for treating vascular inflammation and plaque formation.