Polymorphonuclear leukocyte phagocytic function increases in plasminogen knockout mice

BackgroundMice lacking plasminogen (PG−/−) require alternative pathways of fibrinolysis for survival. This may depend on polymorphonuclear leukocytes (PMN) that can clear soluble and insoluble fibrin(ogen) through PG-independent processes. Our objective was to demonstrate that PMNs from PG−/− mice exhibit increased Mac-1 dependent phagocytic activity, which may explain their increased fibrin(ogen)lytic activity compared with wild type (PG+/+) mice.MethodsPhagocytic activity of PMNs from PG−/− and PG+/+ mice was compared following exposure to Staphylococcus aureus (S. aureus) particles and the expression of Mac-1 was assessed in parallel by flow cytometric analysis. Resistance to phorbol-12-myristate-13-acetate (PMA)-induced cell death was compared between PMNs from the different genotypes.ResultsStimulation of PG−/− PMNs by opsonized S. aureus diluted in PG−/− plasma significantly increased phagocytosis (15-fold) compared with stimulation of PG+/+ PMNs in PG+/+ plasma. Incubation of PG−/− PMNs with PG+/+ plasma (control) or PG−/− plasma supplemented with human PG inhibited this increased phagocytic activity. Mac-1 cell surface density increased 6.2 ± 1.0-fold in PG−/− PMNs versus 2.9 ± 0.6-fold in PG+/+ PMNs (P < 0.01) indicating that Mac-1 may be associated with increased phagocytic activity. Supporting this, treatment of PG−/− PMNs with an anti-Mac-1 antibody in PG−/− plasma inhibited phagocytic activity. In addition, physiologic PG blocked Mac-1 accessibility at the surface of PMNs. Addition of PMA resulted in 33% death of PMNs from PG−/− mice versus 68% in PG+/+ controls (P < 0.001).ConclusionsPMNs from PG−/− mice exhibit a Mac-1 dependent increase in phagocytic activity that is suppressed with human PG, an anti-Mac-1 antibody or the plasma from PG+/+ mice. The propensity for PMNs from PG−/− mice to be activated in response to PMA together with their relative resistance to PMA-toxicity may contribute to increased PMN half-life and enhanced fibrin(ogen) clearance in the setting of PG deficiency.