Abstract
Atopic dermatitis (AD) and psoriasis are clinical manifestations of immune dysregulation in the skin. Psoriasis is generally classified as a T cell-mediated, IFN-γ dependent disease, while AD is skewed toward interleukin (IL)-4 dependence. Consistent with these classifications are clinical observations that IL-4 improves psoriasis disease score and an IL-4 receptor blocking antibody is approved for treatment of severe AD. However, the immunobiology is far more complex, as IL-13, often produced by IL-4 dependent T cells, can be elevated in psoriasis. Since GATA3 controls both IL-4 and IL-13 expression, we propose that regulation of GATA3 differs between the two diseases, resulting in overlapping yet distinct cytokine profiles. Our meta-analysis of two RNA sequencing profiles for each disease identified a noncoding RNA of unknown function (NRUF) in all four datasets (p<1×10−10). Upon analyzing 48 datasets of immune responses to viral infection in epithelial cells and leukocytes, we found IL-13 and NRUF expression levels are most strongly correlated in lymphocytes. In T cell lines, we found elevated expression of the NRUF noncoding RNA associates with IL-4 and IL-13. However, IL-31, which is elevated in AD independently from the GATA3/IL-4/IL-13 axis, is not correlated to NRUF expression, supporting our hypothesis that NRUF drives disease pathology via the GATA3/IL-4/IL-13-dependent inflammatory response. Using overexpression or silencing approaches, we have characterized the ability of this NRUF to direct cytokine polarization of T cells from healthy control and donors with AD or psoriasis. We propose this NRUF modulates these two cutaneous diseases by regulating GATA3-based IL-4/IL-13 balance in T cells.
