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

• Main Authors: Bruscoli, S. (Author), Cardoso, C. (Author), Carvalho, A.F.S (Author), de Oliveira, L.C (Author), Grossi, L.C (Author), Machado, M.G (Author), Morand, E.F (Author), Queiroz-Junior, C.M (Author), Riccardi, C. (Author), Sousa, L.P (Author), Souza, G.V.S (Author), Souza, J.A.M (Author), Tavares, L.P (Author), Teixeira, M.M (Author), Vago, J.P (Author), Zaidan, I. (Author)
• Format: Article
• Language: English
• Published: MDPI 2022
• Subjects: Acute lung injury; animal experiment; animal model; antiinflammatory activity; Article; bacterial clearance; cell infiltration; computer assisted tomography; disease severity; disk diffusion; efferocytosis; fusion protein; gamma interferon; glucocorticoid; high mobility group B1 protein; Inflammation resolution; interleukin 17; interleukin 6; leucine zipper protein; leukocyte count; lipopolysaccharide; lung function; lung injury; minimum inhibitory concentration; mouse; myeloperoxidase; neutrophil chemotaxis; neutrophilic inflammation; nonhuman; phenotype; procalcitonin; Proresolving mediators; protein function; RANTES; Streptococcus pneumonia; Streptococcus pneumoniae; toll like receptor 2; tumor necrosis factor
• Online Access: View Fulltext in Publisher

 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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.