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

项目摘要 皮肤是抵御许多入侵微生物的第一道防线，它不仅起到物理屏障的作用，而且还 作为强大的先天免疫反应的来源。为了避免皮肤中的自身免疫激活，哺乳动物 核酸酶是防止自身核酸先天免疫感知的重要“守护者”。的作用 自身免疫性皮肤病中的核糖核酸酶和核糖核酸降解机制尚不清楚。哺乳动物 胞质RNA外体是由RNA解旋酶、SKIV2L等辅因子组成的多亚基复合体。 SKIV2L功能丧失突变与人类旋毛虫肝肠综合征(THES)相关，以及 这些患者会出现明显的头发和皮肤异常。在初步研究中，我们产生了一种可诱导的 Skiv2l基因敲除小鼠(iSkiv2l-/-)。ISkiv21-/-小鼠出现严重的皮肤炎症以及迅速和显著的 脱发(脱发)。ISkiv2l-/-皮肤病不同于典型的皮炎或牛皮癣，因此代表着一种 新的自身免疫性皮肤病小鼠模型。我们有两个具体目标：目标1.确定细胞类型， 激活iSkiv2l-/-皮肤中的干扰素信号所需的内源性配体和先天感知途径。目标2. 确定I型干扰素的天然免疫激活如何破坏毛囊的免疫豁免权。建议进行的研究 这里将提供令人兴奋的机制洞察力，说明对自我RNA的先天免疫反应如何失调 导致皮肤发炎和毛囊免疫豁免权崩溃。ISkiv2l-/-鼠标还可能具有更广泛的 在了解皮肤中的免疫豁免和耐受性方面的作用，这可能有利于其他自身免疫性皮肤 疾病。

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.