Avaliação do papel da proteína anexina A1 e do seu receptor FPR2 em um modelo murino de pneumonia pneumocócica

Abstract

Pneumococcal pneumonia is the leading cause of community acquired pneumonia and it is responsible for high mortality rates. Pneumonia caused by Streptococcus pneumoniae is characterized by an intense inflammatory response, which is important to eliminate bacteria but can also cause intense tissue damage. In this regard, immunomodulators, like annexin A1 (AnxA1), may be interesting therapeutic targets. AnxA1 is a pro-resolving mediator, mimetized by the synthetic peptide Ac2-26, that by binding on FPR2 receptor, induces neutrophil apoptosis and enhances efferocytosis, among other immunomodulatory effects. Thus, our aim was to access the role of AnxA1 and its receptor FPR2 during the onset of inflammation in a murine model of pneumococcal pneumonia. For this, wild type (WT) and knockout (KO) mice for AnxA1 or FPR2/3 were infected with 5x104 CFU of Streptococcus pneumoniae intranasally and euthanized in different time points post-infection (p.i.) for the assessment of inflammatory and functional parameters. In addition, wild type (WT) mice were infected intranasally with 105 CFU of S. pneumoniae, treated with 6mg/Kg of Ac2-26 and euthanized for inflammation and bacterial assessment. AnxA1 KO mice were more susceptible to the infection, by exhibiting more marked inflammatory response, more bacterial counts and reduced pulmonary function when compared to WT mice. Likewise, FPR2/3 KO mice presented similar parameters of AnxA1 KO, more inflammation, more bacterial counts, worsening of lung function and reduced survival when compared to the WT C57BL/6 mice. Additionally, treatment with Ac2-26 reduced bacterial counts and inflammation. Altogether, the absence of AnxA1 or FPR2/3 contributed to the exacerbated inflammatory response triggered by S. pneumoniae in the lungs. In this regard, AnxA1 active peptide plays an important role controlling inflammation and bacterial proliferation. Therefore, modulation of the inflammatory response can be beneficial during severe pneumococcal pneumonia and treatment with AnxA1 peptidomimetics can be an interesting strategy to control overwhelming inflammation.