NLRP1 inflammasome activation in skin equivalents reveals mechanistic insights into the roles of keratinocytes in psoriasis

Psoriasis is a common inflammatory disease that affects mainly the skin. The pro-inflammatory cytokines interleukin(IL)-1β and IL-36γ are involved in its pathogenesis. However, the molecular and cellular mechanisms underlying the regulation of these pathways in psoriasis are incompletely understood. IL-1β activity is produced downstream of a group of protein complexes termed inflammasomes, which are primarily expressed by immune cells. To address the function of the NLRP1 inflammasome in epidermal keratinocytes, we activated NLRP1 pharmacologically in human skin equivalents (SEs), an organotypic three-dimensional skin model. In the epidermis of these SEs, IL-1β secretion induced a histological phenotype that resembles psoriasis and is associated with a characteristic pro-inflammatory gene expression signature, including the induction of IL-36γ expression and secretion. Whereas expression of IL-36γ is induced by IL-1β, IL-36γ secretion occurs downstream of NLRP1 activation through gasdermin D pores. Most importantly, we detected inflammasome activation in suprabasal keratinocytes in lesional psoriasis. Release of endogenous double stranded (ds) RNA to the cytoplasm is associated with cellular perturbations in several inflammatory conditions, including psoriasis. In keratinocytes in monoculture, we identified short self-derived dsRNA as a novel activator of the NLRP1 inflammasome. These data suggest a critical role of keratinocytes in the pathogenesis of psoriasis through activation of the NLRP1 inflammasome. Furthermore, NLRP1-activated SEs represent a novel in vitro model for this condition, based on human primary skin cells. Most importantly, pharmacological targeting and inhibition of NLRP1 appears as a novel treatment option for psoriasis.