Neutrophil Elastase Mediates Innate Host Protection against Pseudomonas aeruginosa

Abstract

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.

Cathepsin G and Neutrophil Elastase Contribute to Lung-Protective Immunity against Mycobacterial Infections in Mice

“…In line with this finding, CG, NE, and proteinase-3 were recognized to contribute to human neutrophil killing of S. pneumoniae in vitro (11). In addition, NE is important for the elimination of Klebsiella pneumoniae and Escherichia coli as well as Candida albicans and Pseudomonas aeruginosa (8,(12)(13)(14).…”

Neutrophil Elastase Modulates Cytokine Expression

“…At this time point, whereas no death was recorded in WT mice 11 NE Ϫ/Ϫ mice (ϳ45%) died. The survival of the remaining mice was monitored up to 72 h later and in accordance with our previous report (10), ϳ50% of WT mice survived against ϳ20% of NE Ϫ/Ϫ mice.…”

“…The surviving mice (24 WT mice and 10 NE Ϫ/Ϫ mice) were then sacrificed at the 24-h time point, a time that corresponded to maximal PMN infiltration and maximal release of free active NE ( Fig. 1) (10). Control mice were sacrificed 24 h post-saline instillation.…”

“…Although NE has been always regarded as pathogenic in Pseudomonas aeruginosa-associated tissue inflammatory and destructive diseases, we have recently provided compelling in vivo evidence that the enzyme contributes considerably to PMN-mediated host protection in a mouse model of P. aeruginosa-induced pneumonia (10). There is also accumulating evidence that during P. aeruginosa infections, active NE is released in the extracellular milieu by recruited PMNs (13,14).…”

“…Gene targeting of NE in mice revealed that the enzyme contributes significantly to host protection against microbial infections (8). In determining NE-mediated defense against Gram-negative bacteria, it was shown that active enzyme degrades the major outer membrane protein (Omp), structural proteins localized on the cell wall (9,10). NE also has the capacity to attenuate the pathogenicity of invading microbes by targeting their virulence factors (11).…”