Asc and Ipaf Inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila.
Caspase-1 activation is a key feature of the innate immune response of macrophages elicited by pathogens and a variety of toxins. Here, we determined the requirement for different adapter proteins involved in regulating host processes mediated by caspase-1 after macrophage infection by Legionella pneumophila. The adapter protein Asc was found to be important for caspase-1 activation during L. pneumophila infection. Activation of caspase-1 through Asc did not require the flagellin-sensing pathway involving the host nucleotide-binding domain and leucine-rich repeat-containing protein Ipaf (NLRC4). Asc-dependent caspase-1 activation was inhibited by high extracellular potassium levels, whereas Ipaf-dependent activation was unaffected by potassium treatment. Activation of caspase-1 in macrophages occurred independently of Nalp3 and proteasome activity, suggesting that a previously uncharacterized mechanism for caspase-1 activation through Asc may be triggered by L. pneumophila. Rapid pore formation and pyroptosis induced by L. pneumophila required caspase-1, Ipaf, and bacterial flagellin but occurred independently of Asc. Equivalent levels of active interleukin-18 (IL-18) were detected in the lungs of mice infected with a flagellin-deficient strain of L. pneumophila and Asc-deficient mice infected with wild-type L. pneumophila. Active IL-18 was undetectable in the lungs of Asc-deficient mice infected with an L. pneumophila flagellin mutant, indicating independent roles for Ipaf and Asc in caspase-1-mediated processing and release of IL-18 in vivo. Ipaf-dependent activation of caspase-1 restricted bacterial replication in vivo, whereas Asc was dispensable for restriction of L. pneumophila replication in mice. Thus, L. pneumophila-mediated caspase-1 activation involves the coordinate activities of inflammasomes differentially regulated by Ipaf and Asc.
Case
Christopher L
CL
Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. craig.roy@yale.edu
Shin
Sunny
S
Roy
Craig R
CR
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D020170:Caspase 1 / Q000096:biosynthesis*; D003598:Cytoskeletal Proteins / Q000276:immunology*; D005408:Flagellin / Q000276:immunology; D020382:Interleukin-18 / Q000032:analysis; D016952:Legionella pneumophila / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020382:Interleukin-18; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D005408:Flagellin; D020170:Caspase 1