title: An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection.
abstract: Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and -injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf-/- ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Müller
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.|Department of Cell and Molecular Biology, Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Sellin
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Boas
authors.initials: B
authors.lastname: Felmy
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Carolin
authors.initials: C
authors.lastname: Verbree
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gadient
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Westermann
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Vogel
authors.affiliation: Institute of Virology, University of Zürich, Zürich, Switzerland.
authors.forename: Salome
authors.initials: S
authors.lastname: LeibundGut-Landmann
authors.affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D020170:Caspase 1; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D020170:Caspase 1