title: Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens.
abstract: Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1-independent. Instead, caspase-4 mediates IL-1α release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.
authors.affiliation: Departments of Microbiology and.
authors.forename: Cierra N
authors.initials: CN
authors.lastname: Casson
authors.affiliation: Departments of Microbiology and.
authors.forename: Janet
authors.initials: J
authors.lastname: Yu
authors.affiliation: Departments of Microbiology and.
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Reyes
authors.affiliation: Departments of Microbiology and.
authors.forename: Frances O
authors.initials: FO
authors.lastname: Taschuk
authors.affiliation: Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Anjana
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Departments of Microbiology and.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Copenhaver
authors.affiliation: Departments of Microbiology and.
authors.forename: Hieu T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
authors.affiliation: Departments of Microbiology and sunshin@mail.med.upenn.edu.
authors.forename: Sunny
authors.initials: S
authors.lastname: Shin
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000276:immunology; D053471:Caspases, Initiator / Q000276:immunology*; D016923:Cell Death; D002478:Cells, Cultured; D006090:Gram-Negative Bacteria / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016952:Legionella pneumophila / Q000276:immunology / Q000472:pathogenicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D015011:Yersinia pseudotuberculosis / Q000276:immunology / Q000472:pathogenicity
chemical_list: D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: caspase-4; gram-negative bacteria; inflammasome; innate immunity; primary macrophages