title: The shedding-derived soluble receptor for advanced glycation endproducts sustains inflammation during acute Pseudomonas aeruginosa lung infection.
abstract: The membrane-bound isoform of the receptor for advanced glycation end products (FL-RAGE) is primarily expressed by alveolar epithelial cells and undergoes shedding by the protease ADAM10, giving rise to soluble cleaved RAGE (cRAGE). RAGE has been associated with the pathogenesis of several acute and chronic lung disorders. Whether the proteolysis of FL-RAGE is altered by a given inflammatory stimulus is unknown. Pseudomonas aeruginosa causes nosocomial infections in hospitalized patients and is the major pathogen associated with chronic lung diseases.
  
  
  
  P. aeruginosa was injected in Rage-/- and wild-type mice and the impact on RAGE expression and shedding, levels of inflammation and bacterial growth was determined.
  
  
  
  Acute P. aeruginosa lung infection in mice induces a reduction of the active form of ADAM10, which determines an increase of FL-RAGE expression on alveolar cells and a concomitant decrease of pulmonary cRAGE levels. This was associated with massive recruitment of leukocytes and release of pro-inflammatory factors, tissue damage and relocation of cRAGE in the alveolar and bronchial cavities. The administration of sRAGE worsened bacterial burden and neutrophils infiltration. RAGE genetic deficiency reduced the susceptibility to P. aeruginosa infection, mitigating leukocyte recruitment, inflammatory molecules production, and bacterial growth.
  
  
  
  These data are the first to suggest that inhibition of FL-RAGE shedding, by affecting the FL-RAGE/cRAGE levels, is a novel mechanism for controlling inflammation to acute P. aeruginosa pneumonia. sRAGE in the alveolar space sustains inflammation in this setting.
  
  
  
  RAGE shedding may determine the progression of inflammatory lung diseases.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Antonelli
authors.affiliation: Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Maggio
authors.affiliation: Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rejman
authors.affiliation: Department of Pathology, San Raffaele Hospital, Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.affiliation: Infection and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Catucci
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gorzanelli
authors.affiliation: Infection and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy; Università Vita Salute San Raffaele, Milano, Italy. Electronic address: bianchi.marco@hsr.it.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy. Electronic address: arau74@yahoo.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Raucci
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000818:Animals; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology; D008168:Lung / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D000072197:ADAM10 Protein
keywords: Inflammation; P. aeruginosa; Pneumoniae; RAGE shedding; Soluble RAGE