Glucocorticoid-Induced Leucine Zipper Alleviates Lung Inflammation and Enhances Bacterial Clearance during Pneumococcal Pneumonia.

Jéssica Amanda Marques Souza,Stefano Bruscoli,Geovanna V Santos Souza,Leonardo Camilo De Oliveira,Lais C Grossi,Luciana P Tavares,Lirlândia P Sousa,Mauro M Teixeira,Carlo Riccardi,Celso Martins Queiroz-Junior,Marina G Machado,Isabella Zaidan,Camila Cardoso,Juliana P Vago,Antônio Felipe S Carvalho,Eric F Morand

doi:10.3390/cells11030532

Abstract

Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and proresolving bioactions, yet the therapeutical role of GILZ in infectious diseases remains unexplored. Herein, we investigate the role and effects of GILZ during acute lung injury (ALI) induced by LPS and Streptococcus pneumoniae infection. GILZ deficient mice (GILZ−/−) presented more severe ALI, characterized by increased inflammation, decreased macrophage efferocytosis and pronounced lung damage. In contrast, pulmonary inflammation, and damage were attenuated in WT mice treated with TAT-GILZ fusion protein. During pneumococcal pneumonia, TAT-GILZ reduced neutrophilic inflammation and prevented the associated lung damage. There was also enhanced macrophage efferocytosis and bacterial clearance in TAT-GILZ-treated mice. Mechanistically, TAT-GILZ enhanced macrophage phagocytosis of pneumococcus, which was lower in GILZ−/− macrophages. Noteworthy, early treatment with TAT-GILZ rescued 30% of S. pneumoniae-infected mice from lethal pneumonia. Altogether, we present evidence that TAT-GILZ enhances host resilience and resistance to pneumococcal pneumonia by controlling pulmonary inflammation and bacterial loads leading to decreased lethality. Exploiting GILZ pathways holds promise for the treatment of severe respiratory infections.

Highlights

Pneumonia, mainly caused by Streptococcus pneumoniae, is the leading cause of death among children in the world, being responsible for up to 14% of deaths in children under 5 years of age [1]
To uncover the role of GILZ in pulmonary inflammation and injury, we have established a murine mild model of Acute Lung Injury (ALI) that exhibits intense neutrophil infiltration within 12–24 h of the intranasal challenge with LPS but resolves thereafter (Supplementary Figure S1A–C) and investigated the inflammatory response in GILZ deficient mice (GILZ−/− ) compared to WT
The concentrations of TNF-α and IL-6 were increased in Bronchoalveolar Lavage (BAL) fluid after LPS instillation and was markedly higher in GILZ−/− mice (Figure 1E,F)

Summary

Introduction

Mainly caused by Streptococcus pneumoniae, is the leading cause of death among children in the world, being responsible for up to 14% of deaths in children under 5 years of age [1]. S. pneumoniae is an extracellular Gram-positive pathobiont that colonizes mucous surfaces of the superior respiratory tract. S. pneumoniae can disseminate to the lungs and blood causing severe invasive disease [2,3]. Severe pneumococcal pneumonia is characterized by an intense inflammatory response with massive recruitment and activation of leukocytes leading to significant pulmonary damage and bacteria dissemination [4,5]. More than 100 different serotypes of S. pneumoniae have been identified, representing an important challenge for the development of vaccines and therapeutic strategies to control the health burden of pneumococcal infections [6]. Treatment strategies focused on the host immune responses are less susceptible to strain differences and induction of antimicrobial resistance [4]

Methods

Results

Conclusion