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The Pseudomonas aeruginosa protease LasB directly activates IL-1β
Josh Sun1, Doris L LaRock2, Elaine A Skowronski1
1Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, United States.
Background:
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.
Methods:
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.
Findings:
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.
Interpretation:
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.
Funding:
Full details are provided in the Acknowledgements section.
Insights
Pseudomonas aeruginosa infection triggers inflammation via interleukin-1β (IL-1β) activation. The bacterial protease LasB directly activates IL-1β, driving lung damage and offering a new therapeutic target.
Area of Science:
- Microbiology
- Immunology
- Pulmonary Medicine
Background:
- Pseudomonas aeruginosa infections cause lung damage in cystic fibrosis and ventilator-associated pneumonia.
- Host inflammation, driven by interleukin-1β (IL-1β), exacerbates infection, complicated by multidrug resistance.
- The precise mechanisms of IL-1β activation in P. aeruginosa lung infections remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of IL-1β activation during P. aeruginosa pulmonary infection.
- To identify novel pathways regulating inflammation in response to P. aeruginosa.
Main Methods:
- Utilized a pulmonary infection model with P. aeruginosa.
- Employed genetic manipulation, specific protease inhibitors, and recombinant proteins.
- Assessed protease activity and IL-1β bioactivity using targeted reporters.
Main Results:
- Identified plasticity in IL-1β activation, allowing direct maturation by the Pseudomonas aeruginosa protease LasB.
- Demonstrated that LasB promotes IL-1β activation, leading to neutrophilic inflammation.
- Observed LasB-mediated IL-1β activation contributes to lung architecture destruction.
Conclusions:
- Selective control of inflammation is crucial for preserving lung function and immune clearance.
- The discovery of LasB-mediated IL-1β activation presents a novel therapeutic target.
- Matrix metalloprotease inhibitors targeting LasB may limit inflammation and pathology in P. aeruginosa infections.
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