Pseudomonas aeruginosa activates caspase 1 through Ipaf

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 7; pp. 2562 - 2567
• Main Authors: Miao, Edward A, Ernst, Robert K, Dors, Monica, Mao, Dat P, Aderem, Alan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-02-2008; National Acad Sciences
• Subjects: Apoptosis Regulatory Proteins - metabolism; Bacteria; Biological Sciences; Calcium-Binding Proteins - metabolism; Caspase 1 - metabolism; Cells, Cultured; Cytokines; Cytosol; Cytosol - metabolism; Enzyme Activation; Flagellin - pharmacology; Immune system; Infections; Innate immunity; Interleukin-1beta - secretion; Listeria monocytogenes; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - secretion; Monomers; Mutation; Neuronal Apoptosis-Inhibitory Protein - metabolism; Protein Transport; Pseudomonas aeruginosa; Pseudomonas aeruginosa - metabolism; Receptors; Salmonella typhimurium; Secretion; Toll like receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0712183105

The innate immune system encodes cytosolic Nod-like receptors (NLRs), several of which activate caspase 1 processing and IL-1β 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-1β secretion in infected macrophages. While live, virulent P. aeruginosa activate IL-1β 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-1β 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.