ASC acts in a caspase-1-independent manner to worsen acute pneumonia caused by Pseudomonas aeruginosa
Hughes, A. J. and Knoten, C. A. and Morris, A. R. and Hauser, A. R.,, 67, 1168-1180 (2018),
doi = https://doi.org/10.1099/jmm.0.000782,
publicationName = Microbiology Society,
issn = 0022-2615,
abstract= 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-1β. 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-1β 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.,
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