Role of Inflammasome-independent Activation of IL-1β by the Pseudomonas aeruginosa Protease LasB

Abstract

AbstractPulmonary 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 management of these deep-seated infections. Therefore, preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Pathological inflammation during P. aeruginosa pneumonia is driven by interleukin-1β (IL-1β). This proinflammatory cytokine is canonically regulated by caspase-family inflammasome proteases, 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. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such that matrix metalloprotease inhibitors blocking LasB limit inflammation and pathology during P. aeruginosa pulmonary infections.HighlightsIL-1β drives pathology during pulmonary infection by Pseudomonas aeruginosa.The Pseudomonas protease LasB cleaves and activates IL-1β independent of canonical and noncanonical inflammasomesMetalloprotease inhibitors active against LasB limit inflammation and bacterial growthResearch in ContextInflammation is highly damaging during lung infections by the opportunistic pathogen Pseudomonas aeruginosa. Sun et al. demonstrate that the Pseudomonas LasB protease directly activates IL-1β in an inflammasome-independent manner. Inhibition of IL-1β conversion by LasB protects against neutrophilic inflammation and destruction of the lung. Adjunctive therapeutics that limit pathological inflammation induced by infection would be beneficial for the treatment of pulmonary infections when used with conventional antibiotics.