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An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection
Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland..
Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland..
Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland..
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2016 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, no 6, e1005723Article in journal (Refereed) PublishedText
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 12, no 6, e1005723
National Category
Infectious Medicine Microbiology in the medical area
URN: urn:nbn:se:uu:diva-300078DOI: 10.1371/journal.ppat.1005723ISI: 000379345300053PubMedID: 27341123OAI: oai:DiVA.org:uu-300078DiVA: diva2:950733
Swedish Research Council, 2012-262
Available from: 2016-08-02 Created: 2016-08-02 Last updated: 2016-08-02Bibliographically approved

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