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Essentials Plg-R KT is a novel integral membrane plasminogen receptor. The functions of Plg-R KT in vivo are not known. Plg-R KT is a key player in macrophage recruitment in the inflammatory response in vivo. Plg-R KT deficiency is not compatible with survival of the species., Summary: Background Plg-R KT is a novel integral membrane plasminogen receptor that binds plasminogen via a C-terminal lysine exposed on the cell surface and promotes plasminogen activation on the cell surface by both tissue plasminogen activator and urokinase plasminogen activator. Objectives To evaluate the role of Plg-R KT in vivo we generated Plg-R KT -/- mice using a homologous recombination technique. Methods We characterized the effect of Plg-R KT deletion on reproduction, viability, health and spontaneous thrombosis and inflammation. Results Plg-R KT -/- mice were viable and fertile. Survival of Plg-R KT -/- mice and Plg-R KT +/+ littermates was not significantly different. However, quite strikingly, all pups of Plg-R KT -/- females died within 2 days of birth, consistent with a lactation defect in Plg-R KT -/- mothers. Additionally, there was a significant effect of Plg-R KT deficiency on the growth rates of female, but not male, mice. In experimental peritonitis studies, Plg-R KT -/- mice exhibited a marked defect in macrophage recruitment. As a contributing mechanism, the capacity of Plg-R KT -/- macrophages for plasminogen binding was markedly decreased. Conclusions These studies demonstrate that Plg-R KT is required for plasminogen binding and macrophage migration in vivo. In addition, Plg-R KT deficiency is not compatible with survival of the species, due to the death of all offspring of Plg-R KT -/- females. This new mouse model will be important for future studies aimed at delineating the role of cell surface plasminogen activation in challenge and disease models in vivo., Competing Interests: Authors state no conflicts of interests., (© 2016 International Society on Thrombosis and Haemostasis.)

Plasminogen (PLG) is the zymogen of plasmin, the major enzyme that degrades fibrin clots. In addition to its binding and activation on fibrin clots, PLG also specifically interacts with cell surfaces where it is more efficiently activated by PLG activators, compared with the reaction in solution. This results in association of the broad-spectrum proteolytic activity of plasmin with cell surfaces that functions to promote cell migration. Here, we review emerging data establishing a role for PLG, plasminogen receptors and the newly discovered plasminogen receptor, Plg-RKT, in macrophage recruitment in the inflammatory response, and we address mechanisms by which the interplay between PLG and its receptors regulates inflammation., (© 2014 Elsevier Inc. All rights reserved.)

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-R(KT), which exposes a C-terminal lysine on the cell surface. In the present study, we investigated the role of Plg-R(KT) in macrophage invasion, chemotactic migration, and recruitment. Plg-R(KT) was prominently expressed in membranes of human peripheral blood monocytes and monocytoid cells. Plasminogen activation by urokinase-type plasminogen activator (uPA) was markedly inhibited (by 39%) by treatment with anti-Plg-R(KT) mAb. Treatment of monocytes with anti-Plg-R(KT) 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-R(KT) mAb (by 64%). In a mouse model of thioglycollate-induced peritonitis, anti-Plg-R(KT) mAb markedly inhibited macrophage recruitment (by 58%), concomitant with a reduction in pro-MMP-9 activation in the inflamed peritoneum. Treatment with anti-Plg-R(KT) mAb did not further reduce the low level of macrophage recruitment in plasminogen-null mice. We conclude that Plg-R(KT) plays a key role in the plasminogen-dependent regulation of macrophage invasion, chemotactic migration, and recruitment in the inflammatory response.