dc.contributor.author
Bonnekoh, Hanna
dc.contributor.author
Vera, Carolina
dc.contributor.author
Abad‐Perez, Angela
dc.contributor.author
Radetzki, Silke
dc.contributor.author
Neuenschwander, Martin
dc.contributor.author
Specker, Edgar
dc.contributor.author
Mahnke, Niklas Amadeus
dc.contributor.author
Frischbutter, Stefan
dc.contributor.author
Latz, Eicke
dc.contributor.author
Nazaré, Marc
dc.contributor.author
Kries, Jens v.
dc.contributor.author
Maurer, Marcus
dc.contributor.author
Scheffel, Jörg
dc.contributor.author
Krause, Karoline
dc.date.accessioned
2022-11-09T07:03:32Z
dc.date.available
2022-11-09T07:03:32Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/36764
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-36477
dc.description.abstract
Background: The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome-targeting treatment strategies for irritant contact dermatitis.
Methods: A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck-like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)-1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome-mediated cytokines IL-1β and IL-18.
Results: Disulfiram induced a dose-dependent inhibition of ASC speck formation and IL-1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS-induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle (p < 0.001) and/or mometasone (p < 0.001). Also, corneocyte IL-18 levels were significantly reduced after application of disulfiram compared to vehicle (p < 0.001).
Conclusion: We show that disulfiram is a dose-dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS-induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
autoinflammation
en
dc.subject
contact dermatitis
en
dc.subject
inflammasome
en
dc.subject
interleukin-18
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Topical inflammasome inhibition with disulfiram prevents irritant contact dermatitis
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
e12045
dcterms.bibliographicCitation.doi
10.1002/clt2.12045
dcterms.bibliographicCitation.journaltitle
Clinical and Translational Allergy
dcterms.bibliographicCitation.number
5
dcterms.bibliographicCitation.originalpublishername
Wiley
dcterms.bibliographicCitation.volume
11
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
DEAL Wiley
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
34322217
dcterms.isPartOf.eissn
2045-7022