title: Glutaredoxin-1 attenuates S-glutathionylation of the death receptor fas and decreases resolution of Pseudomonas aeruginosa pneumonia.
abstract: BACKGROUND
  The death receptor Fas is critical for bacterial clearance and survival of mice after Pseudomonas aeruginosa infection.
  
  
  OBJECTIVE
  Fas ligand (FasL)-induced apoptosis is augmented by S-glutathionylation of Fas (Fas-SSG), which can be reversed by glutaredoxin-1 (Grx1). Therefore, the objective of this study was to investigate the interplay between Grx1 and Fas in regulating the clearance of P. aeruginosa infection.
  
  
  METHODS
  Lung samples from patients with bronchopneumonia were analyzed by immunofluorescence. Primary tracheal epithelial cells, mice lacking the gene for Grx1 (Glrx1(-/-)), Glrx1(-/-) mice treated with caspase inhibitor, or transgenic mice overexpressing Grx1 in the airway epithelium were analyzed after infection with P. aeruginosa.
  
  
  RESULTS
  Patient lung samples positive for P. aeruginosa infection demonstrated increased Fas-SSG compared with normal lung samples. Compared with wild-type primary lung epithelial cells, infection of Glrx1(-/-) cells with P. aeruginosa showed enhanced caspase 8 and 3 activities and cell death in association with increases in Fas-SSG. Infection of Glrx1(-/-) mice with P. aeruginosa resulted in enhanced caspase activity and increased Fas-SSG as compared with wild-type littermates. Absence of Glrx1 significantly enhanced bacterial clearance, and decreased mortality postinfection with P. aeruginosa. Inhibition of caspases significantly decreased bacterial clearance postinfection with P. aeruginosa, in association with decreased Fas-SSG. In contrast, transgenic mice that overexpress Grx1 in lung epithelial cells had significantly higher lung bacterial loads, enhanced mortality, decreased caspase activation, and Fas-SSG in the lung after infection with P. aeruginosa, compared with wild-type control animals.
  
  
  CONCLUSIONS
  These results suggest that S-glutathionylation of Fas within the lung epithelium enhances epithelial apoptosis and promotes clearance of P. aeruginosa and that glutaredoxin-1 impairs bacterial clearance and increases the severity of pneumonia in association with deglutathionylation of Fas.
authors: 1 Department of Pathology.
authors: Vikas
authors: V
authors: Anathy
authors: Scott W
authors: SW
authors: Aesif
authors: Sidra M
authors: SM
authors: Hoffman
authors: Jenna L
authors: JL
authors: Bement
authors: Amy S
authors: AS
authors: Guala
authors: Karolyn G
authors: KG
authors: Lahue
authors: Laurie W
authors: LW
authors: Leclair
authors: Benjamin T
authors: BT
authors: Suratt
authors: Carlyne D
authors: CD
authors: Cool
authors: Matthew J
authors: MJ
authors: Wargo
authors: Yvonne M W
authors: YM
authors: Janssen-Heininger
mesh_terms: D000818:Animals; D017209:Apoptosis; D058491:Bacterial Load; D015415:Biomarkers / Q000378:metabolism; D001996:Bronchopneumonia / Q000378:metabolism* / Q000382:microbiology; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D054477:Glutaredoxins / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa; D020545:Respiratory Mucosa / Q000378:metabolism / Q000382:microbiology; D012720:Severity of Illness Index; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; C491901:FAS protein, human; C491899:Fas protein, mouse; C516006:Glrx protein, mouse; D054477:Glutaredoxins; D019014:fas Receptor; D020169:Caspases; D005978:Glutathione