The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia
| Autor: | Mauro M. Teixeira, Mauro Perretti, Marina G. Machado, Celso Martins Queiroz-Junior, Mateus Eustáquio Lopes, Fernando R. Ascenção, Geovanna V. Santos Souza, Remo Castro Russo, Lirlândia P. Sousa, Gustavo B. Menezes, Cristiana C. Garcia, Luciana P. Tavares |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine endocrine system Neutrophils Stimulation Inflammation medicine.disease_cause Biochemistry Formyl peptide receptor 2 03 medical and health sciences 0302 clinical medicine Phagocytosis Streptococcus pneumoniae Genetics medicine Animals Receptors Lipoxin Molecular Biology Annexin A1 Mice Inbred BALB C Lung business.industry Macrophages Pneumonia Pneumococcal medicine.disease Receptors Formyl Peptide Mice Inbred C57BL Disease Models Animal Pneumonia 030104 developmental biology medicine.anatomical_structure Pneumococcal pneumonia Immunology medicine.symptom business 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | The FASEB Journal. 34:2749-2764 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.201902172r |
| Popis: | Streptococcus pneumoniae is a major cause of community-acquired pneumonia leading to high mortality rates. Inflammation triggered by pneumococcal infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Annexin A1 (AnxA1) mainly acts through Formyl Peptide Receptor 2 (FPR2) inducing the resolution of inflammation. Here, we have evaluated the role of AnxA1 and FPR2 during pneumococcal pneumonia in mice. For that, AnxA1, Fpr2/3 knockout (KO) mice and wild-type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals. Mechanistically, the absence of AnxA1 resulted in the loss of lung barrier integrity and increased neutrophil activation upon S pneumoniae stimulation. Importantly, treatment of WT or AnxA1 KO-infected mice with Ac2-26 decreased inflammation, lung damage, and bacterial burden in the airways by increasingStreptococcus pneumoniae is a major cause of community-acquired pneumonia leading to high mortality rates. Inflammation triggered by pneumococcal infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Annexin A1 (AnxA1) mainly acts through Formyl Peptide Receptor 2 (FPR2) inducing the resolution of inflammation. Here, we have evaluated the role of AnxA1 and FPR2 during pneumococcal pneumonia in mice. For that, AnxA1, Fpr2/3 knockout (KO) mice and wild-type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals. Mechanistically, the absence of AnxA1 resulted in the loss of lung barrier integrity and increased neutrophil activation upon S pneumoniae stimulation. Importantly, treatment of WT or AnxA1 KO-infected mice with Ac2-26 decreased inflammation, lung damage, and bacterial burden in the airways by increasing macrophage phagocytosis. Conversely, Ac2-26 peptide was ineffective to afford protection in Fpr2/3 KO mice during infection. Altogether, these findings show that AnxA1, via FPR2, controls inflammation and bacterial dissemination during pneumococcal pneumonia by promoting host defenses, suggesting AnxA1-based peptides as a novel therapeutic strategy to control pneumococcal pneumonia. |
| Databáze: | OpenAIRE |
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