Mammalian RNA Exosome in Maintaining Skin Homeostasis and Hair Follicle Immune Privilege

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Project Summary Skin is the first line of defense against many invading microbes, not only acting as a physical barrier, but also acting as a source of powerful innate immune response. To avoid autoimmune activation in the skin, mammalian nucleases act as important ‘guardians’ to prevent innate immune sensing of self-nucleic acids. The role of RNases and RNA degradation machineries in autoimmune skin disease is not well understood. The mammalian cytoplasmic RNA exosome is a multi-subunits complex consists of RNA helicase SKIV2L and other cofactors. SKIV2L lost-of-function mutations are associated with Tricho-hepato-enteric Syndrome (THES) in humans, and THES patients develop remarkable hair and skin abnormalities. In preliminary studies, we generated an inducible Skiv2l knockout mice (iSkiv2l-/-). iSkiv2l-/- mice develop severe skin inflammation as well as rapid and phenomenal hair loss (alopecia). The iSkiv2l-/- skin disease is distinct from typical dermatitis or psoriasis, thus representing a new autoimmune skin disease mouse model. We have two specific aims: Aim 1. Determine the cell type, endogenous ligand and innate sensing pathway required for activating IFN signaling in iSkiv2l-/- skin. Aim 2. Determine how innate immune activation of type I IFN breaks immune privilege of hair follicles. Studies proposed here will provide exciting mechanistic insights in how dysregulated innate immune response to self-RNA could lead to skin inflammation and hair follicle immune privilege collapse. The iSkiv2l-/- mouse may also have broader utility in understanding immune privilege and tolerance in the skin that could benefit other autoimmune skin diseases.