The activation of AIM2/Caspase-1/GSDMD pathway contributes to pyroptosis of keratinocytes in Stevens-Johnson syndrome/toxic epidermal necrolysis

Abstract Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions, rare but life-threatening, characterized by massive keratinocyte death and development of a systemic inflammatory response. Pyroptosis is a lytic form of pro-inflammatory programmed necrotic cell death which participates in the pathogenesis of various inflammatory diseases, it depends on activation of inflammasomes such as NLRP3/NALP1/AIM2/NLRC4 and inflammatory caspases (caspase 1/4/5), subsequently it is executed by pore-forming protein of the gasdermin family, resulting in releases of inflammatory cytokines such as IL-1β, IL-18. However, does pyroptotic machinery exist in the SJS/TEN remains open. In our study, we present evidence for the involvement and mechanism of pyroptosis in SJS/TEN keratinocytes. Inflammatory cytokines TNF-α and IFN-γ participating in keratinocyte pyroptosis through strengthening of cytoplasmic dsDNA/AIM2/Caspase-1/GSDMD pathway were identified in vivo and in vitro. Further, we observed that all of the four small molecular pyroptosis inhibitors including Z-YVAD-FMK，dimethyl fumarate (DMF), necrosulfonamide (NSA) and disulfiram caused a significant inhibition of pyroptosis in human primary keratinocytes, and significantly downregulated the release of pyroptosis-related inflammatory cytokines IL-1β and IL-18. These discoveries expand our understanding of the pathogenesis of SJS/TEN and it is hoped that this could facilitate the development of new therapeutics for the treatment of SJS/TEN patients with activated pyroptosis in keratinocytes.