Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 136, Issue 3, Pages 610-620Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2015.12.022
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Funding
- European Science Foundation (Euro-Membrane program)
- Stiftung fur wissenschaftliche Forschung an der Universitat Zurich
- Center for Clinical Research, University Hospital Zurich
- University of Zurich
- Novartis Foundation
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Inflammasomes are immune complexes that induce an inflammatory response upon sensing of different stress signals. This effect is mainly mediated by activation and secretion of the proinflammatory cytokines proIL-1 beta and -18. Here we report that infection of human primary keratinocytes with the double-stranded DNA viruses modified vaccinia virus Ankara (MVA) or herpes simplex virus type 1 (HSV-1)-induced secretion of mature IL-1 beta and -18. This secretion was dependent on several inflammasome complexes; however, the absent in melanoma 2 (AIM2) inflammasome, which is activated by binding of double-stranded DNA, played the most important role. Whereas prestimulation of keratinocytes with IFN-g moderately increased MVA-induced IL-1 beta and IL-18 secretion, it was essential for substantial secretion of these cytokines in response to herpes simplex virus type 1 infection. IFN-g partially restored HSV-1 suppressed proIL-1 beta expression and was also required for inflammasome activation. Most importantly, IFN-g strongly suppressed virus replication in keratinocytes in vitro and ex vivo, which was independent of inflammasome activation. Our results suggest that, similar to Herpesviridae infection in mice, HSV-1 replication in human skin is controlled by a positive feedback loop of keratinocyte-derived IL-1/IL-18 and IFN-gamma expressed by immune cells.
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