032 IL-36 Axis is a Sex-Biased Immune Amplification Circuit Localized to the Supraspinous Epidermal Compartment

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