title: Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.
abstract: 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.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.forename: Amal
authors.initials: A
authors.lastname: Amer
authors.forename: Mathilde
authors.initials: M
authors.lastname: Body-Malapel
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Nesrin
authors.initials: N
authors.lastname: Ozören
authors.forename: Rajesh
authors.initials: R
authors.lastname: Jagirdar
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.forename: Anthony
authors.initials: A
authors.lastname: Coyle
authors.forename: Ethan P
authors.initials: EP
authors.lastname: Grant
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation; D005408:Flagellin / Q000235:genetics / Q000276:immunology*; D007375:Interleukin-1 / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D007375:Interleukin-1; C512299:Ipaf protein, mouse; D016328:NF-kappa B; D051198:Toll-Like Receptor 5; D005408:Flagellin; D020170:Caspase 1