Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages

• Published in: Nature Immunology 2006-06, Vol.7 (6), p.576-582
• Main Authors: Franchi, Luigi, Amer, Amal, Body-Malapel, Mathilde, Kanneganti, Thirumala-Devi, Ozören, Nesrin, Jagirdar, Rajesh, Inohara, Naohiro, Vandenabeele, Peter, Bertin, John, Coyle, Anthony, Grant, Ethan P, Núñez, Gabriel
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - physiology; Caspase 1 - metabolism; Cytosol - metabolism; Cytosol - microbiology; Enzyme Activation; Flagellin - genetics; Flagellin - immunology; Interleukin-1 - metabolism; Macrophages - enzymology; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Mutant Strains; NF-kappa B - metabolism; Protein Transport; Salmonella; Salmonella Infections - genetics; Salmonella Infections - immunology; Salmonella typhimurium - genetics; Salmonella typhimurium - immunology; Salmonella typhimurium - metabolism; Toll-Like Receptor 5 - genetics; Toll-Like Receptor 5 - physiology
• ISSN: 1529-2908; 1365-2567
• DOI: 10.1038/ni1346

Gram-negative bacteria that replicate in the cytosol of mammalian macrophages can activate a signaling pathway leading to caspase-1 cleavage and secretion of interleukin 1beta, a powerful host response factor. Ipaf, a cytosolic pattern-recognition receptor in the family of nucleotide-binding oligomerization domain-leucine-rich repeat proteins, is critical in such a response to salmonella infection, but the mechanism of how Ipaf is activated by the bacterium remains poorly understood. Here we demonstrate that salmonella strains either lacking flagellin or expressing mutant flagellin were deficient in activation of caspase-1 and in interleukin 1beta secretion, although transcription factor NF-kappaB-dependent production of interleukin 6 or the chemokine MCP-1 was unimpaired. Delivery of flagellin to the macrophage cytosol induced Ipaf-dependent activation of caspase-1 that was independent of Toll-like receptor 5, required for recognition of extracellular flagellin. In macrophages made tolerant by previous exposure to lipopolysaccharide, which abrogates activation of NF-kappaB and mitogen-activated protein kinases, salmonella infection still activated caspase-1. Thus, detection of flagellin through Ipaf induces caspase-1 activation independently of Toll-like receptor 5 in salmonella-infected and lipopolysaccharide-tolerized macrophages.