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IFN-γ primes keratinocytes for HSV-1-induced inflammasome activation


Strittmatter, Gerhard E; Sand, Jennifer; Sauter, Marlies; Seyffert, Michael; Steigerwald, Robin; Fraefel, Cornel; Smola, Sigrun; French, Lars E; Beer, Hans-Dietmar (2016). IFN-γ primes keratinocytes for HSV-1-induced inflammasome activation. Journal of Investigative Dermatology, 136(3):610-620.

Abstract

Inflammasomes are immune complexes, which induce an inflammatory response upon sensing of different stress signals. This effect is mainly mediated by activation and secretion of the proinflammatory cytokines prointerleukin(IL)-1β and -18. Here we report that infection of human primary keratinocytes with the double-stranded (ds) DNA viruses Modified Vaccinia Virus Ankara (MVA) or Herpes Simplex Virus Type 1 (HSV-1) induced secretion of mature IL-1β and -18. This secretion was dependent on several inflammasome complexes, however, the AIM2 inflammasome, which is activated by binding of dsDNA, played the most important role. Whereas prestimulation of keratinocytes with interferon (IFN)-γ moderately increased MVA-induced IL-1β and IL-18 secretion, it was essential for substantial secretion of these cytokines in response to HSV-1 infection. IFN-γ partially restored HSV-1-suppressed proIL-1β expression and was also required for inflammasome activation. Most importantly, IFN-γ 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-γ expressed by immune cells.

Abstract

Inflammasomes are immune complexes, which induce an inflammatory response upon sensing of different stress signals. This effect is mainly mediated by activation and secretion of the proinflammatory cytokines prointerleukin(IL)-1β and -18. Here we report that infection of human primary keratinocytes with the double-stranded (ds) DNA viruses Modified Vaccinia Virus Ankara (MVA) or Herpes Simplex Virus Type 1 (HSV-1) induced secretion of mature IL-1β and -18. This secretion was dependent on several inflammasome complexes, however, the AIM2 inflammasome, which is activated by binding of dsDNA, played the most important role. Whereas prestimulation of keratinocytes with interferon (IFN)-γ moderately increased MVA-induced IL-1β and IL-18 secretion, it was essential for substantial secretion of these cytokines in response to HSV-1 infection. IFN-γ partially restored HSV-1-suppressed proIL-1β expression and was also required for inflammasome activation. Most importantly, IFN-γ 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-γ expressed by immune cells.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
05 Vetsuisse Faculty > Institute of Virology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2016
Deposited On:02 Feb 2016 07:57
Last Modified:22 Dec 2016 14:00
Publisher:Nature Publishing Group
ISSN:0022-202X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jid.2015.12.022
PubMed ID:26739094

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