title: Caspase-1 dependent IL-1β secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection.
abstract: 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.
authors: Division of Pediatrics Infectious Disease and Immunology, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America.
authors: Kenichi
authors: K
authors: Shimada
authors: Timothy R
authors: TR
authors: Crother
authors: Justin
authors: J
authors: Karlin
authors: Shuang
authors: S
authors: Chen
authors: Norika
authors: N
authors: Chiba
authors: V Krishnan
authors: VK
authors: Ramanujan
authors: Laurent
authors: L
authors: Vergnes
authors: David M
authors: DM
authors: Ojcius
authors: Moshe
authors: M
authors: Arditi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000172:deficiency / Q000378:metabolism*; D002690:Chlamydia Infections / Q000150:complications / Q000201:enzymology* / Q000276:immunology*; D016993:Chlamydophila pneumoniae / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000382:microbiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis; D018410:Pneumonia, Bacterial / Q000150:complications / Q000201:enzymology / Q000276:immunology*; D014176:Protein Biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D052247:Nitric Oxide Synthase Type II; D020170:Caspase 1