title: Cutting Edge: Inflammasome Activation in Primary Human Macrophages Is Dependent on Flagellin.
abstract: Murine NLR family, apoptosis inhibitory protein (Naip)1, Naip2, and Naip5/6 are host sensors that detect the cytosolic presence of needle and rod proteins from bacterial type III secretion systems and flagellin, respectively. Previous studies using human-derived macrophage-like cell lines indicate that human macrophages sense the cytosolic needle protein, but not bacterial flagellin. In this study, we show that primary human macrophages readily sense cytosolic flagellin. Infection of primary human macrophages with Salmonella elicits robust cell death and IL-1β secretion that is dependent on flagellin. We show that flagellin detection requires a full-length isoform of human Naip. This full-length Naip isoform is robustly expressed in primary macrophages from healthy human donors, but it is drastically reduced in monocytic tumor cells, THP-1, and U937, rendering them insensitive to cytosolic flagellin. However, ectopic expression of full-length Naip rescues the ability of U937 cells to sense flagellin. In conclusion, human Naip functions to activate the inflammasome in response to flagellin, similar to murine Naip5/6.
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Jens
authors.identifier: http://orcid.org/0000-0003-0848-2377
authors.initials: J
authors.lastname: Kortmann
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Sky W
authors.initials: SW
authors.lastname: Brubaker
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305 dmonack@stanford.edu.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Monack
mesh_terms: D058947:Bacterial Secretion Systems / Q000276:immunology*; D002478:Cells, Cultured; D005408:Flagellin / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000276:immunology*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012475:Salmonella / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology; D020298:U937 Cells
chemical_list: D058947:Bacterial Secretion Systems; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; C496800:NAIP protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; D020033:Protein Isoforms; D005408:Flagellin