Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis

Abstract

Purpose of review: This review compares the fate of monocyte-derived cells that enter atherosclerotic plaques with those that accumulate at other sites of inflammation.

Recent findings: Resolution of inflammatory reactions involves emigration of monocyte-derived cells out of the inflamed site through nearby lymphatic vessels. However, this emigratory process associated with resolution is impaired in atherosclerosis. The mechanism for impeded emigration from plaques in vivo remains to be determined, but multiple factors are likely involved, including specialized properties of artery walls and a negative impact of lipid mediators on monocyte-derived cell migration.

Summary: Impaired egress would be expected to compound macrophage accumulation within plaques, contribute to build-up of necrotic pools, and explain in part the reticence of many plaques to regress, or resolve. Restoration of the capacity of monocyte-derived cells to leave plaques would, by contrast, be expected to facilitate regression, but it remains to be determined whether restoring egress may sometimes provoke unwanted outcomes as well.

Figure 1. Diagram of atherosclerotic plaque as it pertains to the possible routes by which immune cells may emigrate from the plaque or overall aortic wall, including the adventitia

Monocyte-derived cells typically exit tissues through lymphatic vessels, but elasticized medial layers comprise an imposing barrier to leukocyte trafficking, and accordingly, few leukocytes are found in the medial layers beneath plaques. The relative inaccessibility of the lymphatic network may favor egress of monocyte-derived cells through the overlying arterial endothelium, returning the escaping phagocyte to the bloodstream. Escape of monocyte-derived cells in general appears to be rare in plaques that progress to greater size and complexity, and instead this migratory process may mainly characterize regressing, or resolving, plaques.

Figure 2. A new method to track whether monocyte-derived cells leave plaques

Cartoon depicts cross-sections of an artery containing a raised area corresponding with an atherosclerotic plaque. Nonbiodegradable latex beads are used to label circulating monocyte subsets in mice (labeled monocytes depicted as red spheres, time point 1). These monocytes carry the label out of the bloodstream as they enter tissues, such as inflamed atherosclerotic plaques. Labeled monocytes are largely cleared from the circulation during a 5-day time period (time point 2), as they are recruited to tissues and undergo normal turnover. Because the label cannot be lost from plaques if monocyte-derived cells die, any subsequent loss of the label within plaques after an initial plateau during recruitment would indicate egress of phagocytes from the plaque (time point 3, right). This egress may occur through the bloodstream or involve migration to distal sites like lymph nodes (time point 3, boxed area). By contrast, persistence of the label to the same level as the initial plateau following recruitment would indicate little to no emigration out of plaques (time point 3, left).