032 IL-36 axis is a sex-biased immune amplification circuit localized to the supraspinous epidermal compartment

Both psoriasis and pustular are characterized by prominent involvement of IL-36 family cytokines, which consists three pro-inflammatory cytokines: IL-36A, IL-36B IL-36G, the receptor antagonist (IL-36RA/IL36RN). cytokines significantly increased in psoriatic skin, on average about 5-10-fold elevated forms psoriasis. Using single-cell spatial-seq approaches we have demonstrated that responses primarily localized to supraspinous compartment epidermis, strongly correlate with, act downstream of, both IL-17A TNF responses. Deletion each members using CRISPR/Cas9 targeted KO keratinocytes, demonstrate IL36G IL36R KOs, but not IL36A KO, markedly suppress (p<0.001), compared WT keratinocytes. Notably, suppressive role occurred absence neutrophil proteases, been considered primary activators axis skin. Furthermore, bulk RNA-seq data from keratinocytes (n=47) showed marked sex bias IL-36G response, with female having a more robust response (p<0.001). These provide novel insights into biology, its amplifying IL-17 within suggest sex-bias underlie female-bias