Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 5; pp. 1851 - 1856
• Main Authors: Case, Christopher L., Kohler, Lara J., Lima, Jonilson B., Strowig, Till, de Zoete, Marcel R., Flavell, Richard A., Zamboni, Dario S., Roy, Craig R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.01.2013; National Acad Sciences
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; agonists; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bacteria; Biological Sciences; Bone Marrow Cells - metabolism; Bone Marrow Cells - microbiology; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; CARD Signaling Adaptor Proteins; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 1 - genetics; Caspase 1 - metabolism; caspase-1; caspase-11; Caspases - genetics; Caspases - metabolism; Cells; Cells, Cultured; Cytokines - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Enzyme Activation; flagellin; Flagellin - genetics; Flagellin - metabolism; Host-Pathogen Interactions; Immunoblotting; Legionella pneumophila; Legionella pneumophila - genetics; Legionella pneumophila - metabolism; Legionella pneumophila - physiology; macrophages; Macrophages - cytology; Macrophages - metabolism; Macrophages - microbiology; Medical treatment; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Necrosis; NLR Family, Pyrin Domain-Containing 3 Protein; Pathogens; Proteins; rapid methods; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; type IV secretion system
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1211521110

A flagellin-independent caspase-1 activation pathway that does not require NAIP5 or NRLC4 is induced by the intracellular pathogen Legionella pneumophila . Here we demonstrate that this pathway requires caspase-11. Treatment of macrophages with LPS up-regulated the host components required for this caspase-11 activation pathway. Activation by Legionella differed from caspase-11 activation using previously described agonists in that Legionella caspase-11 activation was rapid and required bacteria with a functional type IV secretion system called Dot/Icm. Legionella activation of caspase-11 induced pyroptosis by a mechanism independent of the NAIP/NLRC4 and caspase-1 axis. Legionella activation of caspase-11 stimulated activation of caspase-1 through NLRP3 and ASC. Induction of caspase-11–dependent responses occurred in macrophages deficient in the adapter proteins TRIF or MyD88 but not in macrophages deficient in both signaling factors. Although caspase-11 was produced in macrophages deficient in the type-I IFN receptor, there was a severe defect in caspase-11–dependent pyroptosis in these cells. These data indicate that macrophages respond to microbial signatures to produce proteins that mediate a capsase-11 response and that the caspase-11 system provides an alternative pathway for rapid detection of an intracellular pathogen capable of evading the canonical caspase-1 activation system that responds to bacterial flagellin.