Differential expression of Plg-RKT and its effects on migration of proinflammatory monocyte and macrophage subsets

Membrane-bound plasmin is used by immune cells to degrade extracellular matrices, which facilitates migration. The plasminogen receptor Plg-R-KT is expressed by immune cells, including monocytes and macrophages. Among monocytes and macrophages, distinct subsets can be distinguished based on cell surface markers and pathophysiological function. We investigated expression of Plg-R-KT by monocyte and macrophage subsets and whether potential differential expression might have functional consequences for cell migration. Proinflammatory CD14(++)CD16(+) human monocytes and Ly6C(high) mouse monocytes expressed the highest levels of Plg-R-KT and bound significantly more plasminogen compared with the other respective subsets. Proinflammatory human macrophages, generated by polarization with lipopolysaccharide and interferon-gamma, showed significantly higher expression of Plg-R-KT compared with alternatively activated macrophages, polarized with interleukin-4 and interleukin-13. Directional migration of proinflammatory monocytes was plasmin dependent and was abolished by anti-Plg-R-KT monoclonal antibody, epsilon-amino-caproic acid, aprotinin, and the amino-terminal fragment of urokinase-type plasminogen activator. In an in vivo peritonitis model, significantly less Ly6Chigh monocyte recruitment was observed in Plg-R-KT(-/-) compared with Plg-R-KT(+/+) mice. Immunohistochemical analysis of human carotid plaques and adipose tissue showed that proinflammatory macrophages also exhibited high levels of Plg-R-KT in vivo. Our data demonstrate higher expression of Plg-R-KT on proinflammatory monocyte and macrophage subsets that impacts their migratory capacity.