Topical inflammasome inhibition with disulfiram prevents irritant contact dermatitis

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.