Plasmin modulates neutrophilic inflammation and alveolar macrophage function, protecting mice from pneumococcal pneumonia

ABSTRACT: Accumulating evidence supports the proresolving actions of the plasminogen/plasmin (Plg/Pla) system during inflammation, beyond its classical role in fibrin degradation. Here, we investigated the role of Plg/Pla on key features of inflammation resolution in a murine model of severe pneumococcal pneumonia. High levels of Plg were observed in the airways after infection, accompanied by increased levels of Plg activator inhibitor-1, neutrophil elastase, and Plg degradation fragments as inflammation progressed. Pla treatment of mice infected with Streptococcus pneumoniae decreased neutrophilic infiltration in airways and lungs, accompanied by lower concentrations of the neutrophil chemoattractive chemokines CXCL1 and CXCL2 and the proinflammatory cytokines tumor necrosis factor, interleukin-6 (IL-6), and IL-1β. Pla treatment also enhanced neutrophil apoptosis and efferocytosis and slightly reduced bacterial loads in bronchoalveolar lavage. In addition, Pla decreased damage and fibrin deposition in the lungs, improving pneumonia-driven pulmonary mechanical dysfunction and rescuing mice from lethality. Pla-induced resolution of S pneumoniae-evoked inflammation was associated with neutrophil apoptosis, as the caspase-3-specific inhibitor Z-DEVD-FMK blocked Pla-protective actions. In addition to the effects on neutrophils, intranasal instillation of Pla in naive mice increased the number of alveolar macrophages and guided them toward a regulatory phenotype marked by enhanced efferocytosis of apoptotic neutrophils and increased bacterial phagocytosis, ultimately promoting host protection against pneumococcus-induced inflammation and tissue damage. In sum, our findings demonstrate that Pla modulates the lung inflammatory milieu and promotes key proresolving events, namely neutrophil apoptosis and expansion of alveolar macrophage with enhanced efferocytosis and phagocytic abilities, resulting in improved lung function and survival in pneumococcal pneumonia.