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ASC acts in a caspase‐1‐independent manner to worsen acute pneumonia caused by Pseudomonas aeruginosa

Purpose. Pseudomonas aeruginosa expresses a type III secretion system (T3SS) that activates the host inflammasome‐mediated immune response. We examined the role of inflammasome activation in severe infection outcomes. Methods. We infected C57BL/6 (B6) mice lacking inflammasome components ASC or caspase‐1/11 with a highly virulent strain of P. aeruginosa, PSE9, using a mouse model of pneumonia. We evaluated inflammasome activation in vitro by infecting bone marrow‐derived macrophages (BMDMs) with PSE9 and measuring cell death and release of inflammasome‐dependent cytokines IL‐18 and IL‐1&bgr;. A bioluminescent reporter assay was used to detect activity of caspase‐1 and caspase‐3/7 in BMDMs from B6 and ASC‐deficient mice. Results/Key Findings. ASC−/− mice exhibited significantly improved survival relative to caspase‐1/11−/− mice and B6 mice, demonstrating that ASC and caspase‐1/11 play differential roles in P. aeruginosa infection. We found that ASC−/− BMDMs exhibited significantly reduced cell death relative to B6 BMDMs, while caspase‐1/11−/− BMDMs were resistant to cell death. IL‐18 and IL‐1&bgr; were both detected from supernatants of infected B6 BMDMs, but cytokine release was abrogated in both ASC−/− and caspase‐1/11−/− BMDMs. We detected a 2.5‐fold increase in the activation of caspase‐3/7 in PSE9‐infected B6 BMDMs, but no increase in infected ASC−/− BMDMs. Cell death, cytokine release and caspase‐3/7 activity were dependent on a functional T3SS. Conclusions. Collectively, these results are consistent with a model whereby the T3SS apparatus of P. aeruginosa activates the caspase‐1‐dependent inflammasome and caspase‐3/7 through an ASC‐dependent mechanism. This activation may have implications for the outcomes of P. aeruginosa infections.