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Caspase-1 dependent IL-1β secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection
PLoS One
  • Kenichi Shimada, Cedars-Sinai Medical Center
  • Timothy R. Crother, Cedars-Sinai Medical Center
  • Justin Karlin, Cedars-Sinai Medical Center
  • Shuang Chen, Cedars-Sinai Medical Center
  • Norika Chiba, Cedars-Sinai Medical Center
  • V. Krishnan Ramanujan, Cedars-Sinai Medical Center
  • Laurent Vergnes, University of California, Los Angeles
  • David M. Ojcius, University of California, Merced
  • Moshe Arditi, Cedars-Sinai Medical Center
David M. Ojcius: 0000-0003-1461-4495
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Chlamydia pneumoniae (CP) is an important human pathogen that causes atypical pneumonia and is associated with various chronic inflammatory disorders. Caspase-1 is a key component of the ‘inflammasome’, and is required to cleave pro-IL-1β to bioactive IL-1β. Here we demonstrate for the first time a critical requirement for IL-1β in response to CP infection. Caspase-1−/− mice exhibit delayed cytokine production, defective clearance of pulmonary bacteria and higher mortality in response to CP infection. Alveolar macrophages harbored increased bacterial numbers due to reduced iNOS levels in Caspase-1−/− mice. Pharmacological blockade of the IL-1 receptor in CP infected wild-type mice phenocopies Caspase-1-deficient mice, and administration of recombinant IL-1β rescues CP infected Caspase-1−/− mice from mortality, indicating that IL-1β secretion is crucial for host immune defense against CP lung infection. In vitro investigation reveals that CP-induced IL-1β secretion by macrophages requires TLR2/MyD88 and NLRP3/ASC/Caspase-1 signaling. Entry into the cell by CP and new protein synthesis by CP are required for inflammasome activation. Neither ROS nor cathepsin was required for CP infection induced inflammasome activation. Interestingly, Caspase-1 activation during CP infection occurs with mitochondrial dysfunction indicating a possible mechanism involving the mitochondria for CP-induced inflammasome activation.
Article e21477
Citation Information
Kenichi Shimada, Timothy R. Crother, Justin Karlin, Shuang Chen, et al.. "Caspase-1 dependent IL-1β secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection" PLoS One Vol. 6 Iss. 6 (2011) p. 1 - 13 ISSN: 1932-6203
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