PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Regulation of macrophage migration by a novel plasminogen receptor Plg-RKT

Localization of plasmin on macrophages and activation of pro–MMP-9 play key roles in macrophage recruitment in the inflammatory response. These functions are promoted by plasminogen receptors exposing C-terminal basic residues on the macrophage surface. Recently, we identified a novel transmembrane plasminogen receptor, Plg-RKT, which exposes a C-terminal lysine on the cell surface. In the present study, we investigated the role of Plg-RKT in macrophage invasion, chemotactic migration, and recruitment. Plg-RKT was prominently expressed in membranes of human peripheral blood monocytes and monocytoid cells. Plasminogen activation by urokinasetype plasminogen activator (uPA) was markedly inhibited (by 39%) by treatment with anti–Plg-RKT mAb. Treatment of monocytes with anti–Plg-RKT mAb substantially inhibited invasion through the representative matrix, Matrigel, in response to MCP-1 (by 54% compared with isotype control). Furthermore, chemotactic migration was also inhibited by treatment with anti–Plg-RKT mAb (by 64%). In a mouse model of thioglycollate-induced peritonitis, anti–Plg-RKT mAb markedly inhibited macrophage recruitment (by 58%), concomitant with a reduction in pro–MMP-9 activation in the inflamed peritoneum. Treatment with anti–Plg-RKT mAb did not further reduce the low level of macrophage recruitment in plasminogennull mice. We conclude that Plg-RKT plays a key role in the plasminogen-dependent regulation of macrophage invasion, chemotactic migration, and recruitment in the inflammatory response. (Blood. 2011; 118(20):5622-5630)