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

Abstract

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-γ, 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, ε-amino-caproic acid, aprotinin, and the aminoterminal fragment of urokinase-type plasminogen activator. In an in vivo peritonitis model, significantly less Ly6C^high 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.