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

The pro-inflammatory cytokines interleukin(IL)-1β and IL-36γ are key drivers of psoriasis, an inflammatory skin disease for which a causal therapy is not available. However, the mechanisms underlying regulation of these cytokines in psoriasis remain poorly understood. Generation of IL-1β activity is regulated by inflammasomes. We activated the NLRP1 inflammasome in human keratinocytes cultivated in three-dimensional skin equivalents. NLRP1 activation induced histological and molecular features highly reminiscent of psoriasis. Mechanistically, the phenotype was dependent on IL-1, which triggered a pro-inflammatory epidermal-dermal crosstalk. This included induction of IL-36γ expression, which was released from keratinocytes through NLRP1 inflammasome-induced gasdermin D pores. The relevance of these findings is reflected by the expression of NLRP1 and inflammasome activation in lesions of psoriasis patients. Finally, we discovered endogenous cytoplasmic double stranded (ds) RNA, recently associated with cellular perturbations in psoriasis, as a novel NLRP1 activator. Our results identify a novel endogenous dsRNA-mediated NLRP1-IL-1-IL-36γ signaling axis relevant in psoriasis and suggest its targeting as a promising treatment strategy.