Elucidating The Role Of Innate Immunity Involving Interleukin-1 Cytokines And Inflammasome Signaling Pathways In The Pathogenesis Of Psoriasis

Interleukin-1 family cytokines, as the central mediators of innate and adaptive immunity, are important in the pathogenesis of psoriasis. The inflammasome is a multiprotein complex that assembles the adaptor protein, apoptosis-associated speck-like protein with caspase activation and recruitment domain (ASC) to activate procaspase-1 to release mature IL-1β. However, the mechanistic steps governing inflammasome activation in keratinocytes in inflammatory conditions have not been studied in detail. Skin biopsies and serum samples were obtained from 6 psoriatic and 6 control patients. Using immunohistochemistry to examine the sub-cellular localization of ASC in psoriatic inflammation, we showed ASC was notably cytoplasmic in psoriatic lesional skin, but nuclear in normal and psoriatic non-lesional skin. This cytoplasmic translocation of ASC was similarly demonstrated in murine skin treated with topical imiquimod to induce psoriasis-like inflammation versus petrolatum-treated murine skin. Furthermore, pro-inflammatory cytokines of TNF-α and IL-17 acted together to directly cause ASC translocation in-vitro using ASC-GFP expressing immortalized keratinocytes and immunofluorescence. ELISA measurements of cytokines revealed a trend towards higher IL-1β within the sera of psoriatic patients and cultured keratinocytes derived from psoriatic lesional skin, compared with healthy controls. In contrast, IL-1α levels tended to be decreased. Our study highlights a link between innate and acquired immunity in plaque psoriasis, where the TH17-dominant pro-inflammatory milieu may prime the inflammasome complex in lesional keratinocytes—using ASC cytosolic translocation as a novel regulatory mechanism—thereby, triggering the release of IL-1 cytokines, which act synergistically with the TH17 downstream pathway, to drive psoriasis inflammation.