MicroRNAs in atopic dermatitis pathogenesis: a role for mast cell and sphingosine-1-phosphate?

 特应性皮炎(AD)，又称湿疹，以过敏性皮肤炎症为特征，伴有免疫细胞重塑和聚集，包括T细胞和肥大细胞(MC)，但其发病机制尚不清楚。顽固性瘙痒是AD患者最常见的现象，与不良的生活质量有关。据报告，儿童和成人的患病率在世界范围内不断上升，分别影响到每个人口的至少15%和2%-10%。不幸的是，与湿疹相关的高残疾负担仍然存在。在许多AD病例中，湿疹缓解不足和当前局部治疗缺乏临床疗效，加上免疫抑制药物的有害副作用，引发了许多正在进行的治疗研究，强调了对AD更好的药理选择的医学需求尚未得到满足。由于其炎性成分需要多种分子途径的协同作用，我们推测microRNAs是最近被认为是通过mRNA靶向而被认为是疾病过程中强有力的表观遗传调节的非编码小RNA，在AD发展过程中观察到的基因和蛋白质表达的时空调控中可能发挥重要作用。关于AD中发生的这种表观遗传变化，我们知之甚少。此外，尽管80%的AD患者表现出高水平的循环免疫球蛋白(Ig)E(过敏患者中检测到的Ig同型)，但AD的过敏成分仍然存在争议。位于血管周围的皮肤常驻MC是过敏反应的关键效应者，在人类和小鼠的AD皮损中，MC的数量增加。我们发现，变应原使MC表达高亲和力的Ig E受体(FcεRI)，从而触发MC激活，随后释放与STAT3转录因子相关的趋化因子，并激活鞘氨醇-1-磷酸(S1P)酶，后者是一种强大的炎症和趋化脂质介质。利用一个成熟的类AD小鼠模型，我们已经确定了一组在炎症皮肤中持续下调的三个miRNAs，这导致了参与MC生物学和免疫细胞募集的许多靶基因的上调。本应用的目的是：建立阿尔茨海默病发病时的miRNA图谱及其与MC功能的关系；阐明由miRNA三联体控制的信号通路及其与S1P和趋化因子的产生以及MC激活的相关性。我们期待我们提出的研究将提供证据，证明表观遗传学在调控AD启动中的重要性，包括MC和S1P通过STAT3介导的趋化因子产生对炎性细胞募集的作用，从而导致AD的进展。我们建议这些机械性的洞察力将确定新的分子靶点来预防AD。

 DESCRIPTION (provided by applicant) Atopic dermatitis (AD), also called eczema, is characterized by allergic skin inflammation with remodeling and accumulation of immune cells, including T cells and mast cells (MC), but its pathogenesis remains poorly understood. Recalcitrant itching is most common and associated with poor quality of life for AD patients. Rising world-wide prevalence has been reported among children and adults, affecting at least 15% and 2-10% of each population, respectively. The high burden of disability related to eczema remains unfortunately consistent. In many AD cases, insufficient eczema relief and lack of clinical efficacy of current topical treatments, associated with deleterious side effects of immunosuppressive drugs have triggered many ongoing treatment studies, emphasizing the unmet medical need for better pharmacological options in AD. Because of its inflammatory components requiring the coordinated actions of diverse molecular pathways, we reasoned that microRNAs, small non coding RNAs recently recognized as potent epigenetic regulators of disease processes through mRNA targeting, could exert important functions in the spatiotemporal control of gene and protein expression observed during the development of AD. Little is known pertaining to such epigenetic changes occurring in AD. In addition, even though 80% of AD patients display high levels of circulating immunoglobulin (Ig) E, the Ig isotype detected in allergic patients, the allergic component of AD remains controversial. Located around blood vessels, skin-resident MC are key effectors of allergic reactions, increased in number in AD skin lesions of humans and mice. We have discovered that crosslinking of MC expressed high affinity receptors for IgE (FcεRI) by allergen triggers MC activation, subsequent release of chemokines linked to Stat3 transcription factor and activation of sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate (S1P), a potent inflammatory and chemotactic lipid mediator. Using a well-established AD-like mouse model, we have identified a set of three miRNAs consistently downregulated in inflamed skins which leads to the up-regulation of many target genes involved in MC biology and immune cell recruitment. The objectives of this application are: to establish the miRNA profiling at the onset of AD and its association with MC functions; to elucidate the signaling pathways controlled by the miRNA triad and their relevance to S1P and chemokine production and MC activation. We anticipate our proposed studies will provide evidence for the importance of epigenetics in the regulation of AD initiation involving MC and S1P contributions to inflammatory cell recruitment through Stat3-mediated chemokine production, hence leading to AD progression. We are proposing these mechanistic insights will identify new molecular targets to prevent AD.