title: Pseudomonas aeruginosa activates caspase 1 through Ipaf.
abstract: The innate immune system encodes cytosolic Nod-like receptors (NLRs), several of which activate caspase 1 processing and IL-1beta and IL-18 secretion. Macrophages respond to Salmonella typhimurium infection by activating caspase 1 through the NLR Ipaf. This activation is mediated by cytosolic flagellin through the activity of the virulence-associated type III secretion system (T3SS). We demonstrate here that Pseudomonas aeruginosa activates caspase 1 and induces IL-1beta secretion in infected macrophages. While live, virulent P. aeruginosa activate IL-1beta secretion through caspase 1 and Ipaf, strains that have mutations in the T3SS or in flagellin did not. Ipaf-dependent caspase 1 activation could be recapitulated by delivering P. aeruginosa flagellin to the macrophage cytosol. We examined the role of Naip5 in P. aeruginosa-induced caspase 1 activation by using A/J (Naip5-deficient) compared with C57BL/6 and BALB/c (Naip5-sufficient) macrophages and observed that A/J macrophages secrete IL-1beta in response to P. aeruginosa, S. typhimurium, and Listeria monocytogenes infection, as well as in response to cytosolic flagellin, but at slightly reduced levels. Thus, Ipaf-dependent detection of cytosolic flagellin is a conserved mechanism by which macrophages detect the presence of pathogens that use T3SS.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.forename: Monica
authors.initials: M
authors.lastname: Dors
authors.forename: Dat P
authors.initials: DP
authors.lastname: Mao
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D005408:Flagellin / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000378:metabolism; D021381:Protein Transport; D011550:Pseudomonas aeruginosa / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D005408:Flagellin; D020170:Caspase 1