Neutrophil elastase mediates innate host protection against Pseudomonas aeruginosa.
According to the widely accepted view, neutrophil elastase (NE), a neutrophil-specific serine protease, is a major contributor to Pseudomonas aeruginosa infection-associated host tissue inflammation and damage, which in severe cases can lead to death. Herein, we provide for the first time compelling evidence that the host rather employs NE to protect itself against P. aeruginosa infection. Using a clinically relevant model of pneumonia, targeted deficiency in NE increased the susceptibility of mice to P. aeruginosa. We found that NE was required for maximal intracellular killing of P. aeruginosa by neutrophils. In investigating the mechanism of NE-mediated killing of P. aeruginosa, we found that NE degraded the major outer membrane protein F, a protein with important functions, including porin activity, maintenance of structural integrity, and sensing of host immune system activation. Consistent with this, the use of an isogenic mutant deficient in outer membrane protein F negated the role of NE in host defense against P. aeruginosa infection.
Hirche
Tim O
TO
Institut National de la Santé et de la Recherche Médicale, Programme Avenir, IFR53, University of Reims Champagne-Ardenne, Reims, France.
Benabid
Rym
R
Deslee
Gaetan
G
Gangloff
Sophie
S
Achilefu
Samuel
S
Guenounou
Moncef
M
Lebargy
François
F
Hancock
Robert E
RE
Belaaouaj
Azzaq
A
D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D018410:Pneumonia, Bacterial / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D011552:Pseudomonas Infections / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D001425:Bacterial Outer Membrane Proteins; D019272:Leukocyte Elastase