The Pseudomonas aeruginosa protease LasB directly activates IL-1β

• Published in: EBioMedicine 2020-10, Vol.60, p.102984-102984, Article 102984
• Main Authors: Sun, Josh, LaRock, Doris L., Skowronski, Elaine A., Kimmey, Jacqueline M., Olson, Joshua, Jiang, Zhenze, O'Donoghue, Anthony J., Nizet, Victor, LaRock, Christopher N.
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; Cystic Fibrosis - complications; Cystic Fibrosis - pathology; Cytokines - metabolism; Disease Models, Animal; Enzyme Activation; Host-Pathogen Interactions; IL-1β; Immunohistochemistry; Inflammasomes - metabolism; Inflammation; Inflammation Mediators; Interleukin-1beta - metabolism; Lung; Metalloprotease inhibitor; Metalloproteases - antagonists & inhibitors; Mice; Mice, Knockout; Models, Biological; Pneumonia, Bacterial - etiology; Pneumonia, Bacterial - metabolism; Pneumonia, Bacterial - pathology; Protein Binding; Proteolysis; Pseudomonas aeruginosa; Pseudomonas aeruginosa - enzymology; Pseudomonas Infections - etiology; Pseudomonas Infections - metabolism; Pseudomonas Infections - pathology; Research paper; Serine Endopeptidases - metabolism
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2020.102984

Pulmonary damage by Pseudomonas aeruginosa during cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates the management of these deep-seated infections. Pathological inflammation during infection is driven by interleukin-1β (IL-1β), but the molecular processes involved are not fully understood. We examined IL-1β activation in a pulmonary model infection of Pseudomonas aeruginosa and in vitro using genetics, specific inhibitors, recombinant proteins, and targeted reporters of protease activity and IL-1β bioactivity. Caspase-family inflammasome proteases canonically regulate maturation of this proinflammatory cytokine, but we report that plasticity in IL-1β proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1β activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severe P. aeruginosa pulmonary infection. Preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such as matrix metalloprotease inhibitors that inhibit LasB and limit inflammation and pathology during P. aeruginosa pulmonary infections. Full details are provided in the Acknowledgements section.