The role of IL-33 in regulating skin immunity and skin carcinogenesis

Abstract

Lymphoid stress-surveillance (LSS) refers to the capacity of tissue resident intraepithelial lymphocytes (IEL) to directly sense epithelial cell (EC) dysregulation and initiate a reparative response. Dendritic epidermal T cells (DETC) in the skin are potent producers of IL-13 upon epithelial dysregulation, which regulates EC function, promotes tissue homeostasis and protects against skin carcinogenesis. This may be due to its prominent effect on basal EC, where IEL-derived IL-13 enables a canonical EC stress-response with the expression of Il33 RNA. IL-33 is an abundant cytokine ‘alarmin’ which is constitutively expressed in the nucleus of basal skin EC but is rapidly released upon epithelial challenge. Here I show that LSS in the skin regulates the expression of IL-33 protein in EC during health as well as its release following epithelial damage. LSS does not regulate the fellow family member epithelial alarmin, IL-1, in EC. The IL-33 receptor, ST2, is predominantly expressed on skin resident and infiltrating regulatory T cells (TReg), with skin ST2+TReg localizing in close association with IL-33+ basal EC. I demonstrate that ST2-signalling in skin TReg promotes a more immunosuppressive and reparative phenotype in these cells. Absence of the IL-33/ST2 axis alters EC differentiation and phenotype, with EC aberrantly expressing stress-antigens, distinct keratins and pro-inflammatory cytokines, and the tissue displays reduced barrier integrity, as demonstrated by an increase in trans-epidermal water loss. Moreover, IL-33/ST2-signalling aids in restoring the skin barrier after epidermal abrasion by tape stripping, regulates immune infiltration during skin inflammation and protects against EC tumour outgrowth during cutaneous two-stage chemical carcinogenesis. Together my findings suggest, that IL-33, downstream of LSS, mediate direct EC-TReg cross-communication, and that this molecular axis further supports tissue homeostasis and protects against skin cancer development.