Plasmin modulates neutrophilic inflammation and alveolar macrophage function, protecting mice from pneumococcal pneumonia
Abstract
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.
Article Details
Authors (26)
Camila Cardoso
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Antônio Felipe S. Carvalho
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Edvaldo S. Lara
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Fernanda S. Carneiro
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Isabella Zaidan
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Laís C. Grossi
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Ana Clara M. Montuori-Andrade
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Jessica A. M. Souza
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Franciel B. Felix
3Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Adelson Héric A. Monteiro
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Erick B. Lima
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Isabella L. Augusto
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Rodrigo S. Caixeta
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Bárbara C. M. Barbosa
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Celso M. Queiroz-Junior
3Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Remo C. Russo
4Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Vanessa Pinho
3Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Juliana P. Vago
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Michelle A. Sugimoto
5PulmoBioMed Ltd, Newcastle upon Tyne, United Kingdom
Vivian V. Costa
3Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Lindsey A. Miles
6Department of Molecular Medicine, Scripps Research, La Jolla, CA
Robert J. Parmer
7Department of Medicine, Veterans Administration San Diego Healthcare System, San Diego, CA
Fernão C. Braga
2Programa de Pós-graduação de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Mauro M. Teixeira
Luciana P. Tavares
10Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
Lirlândia P. Sousa
1Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil