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

 特应性皮炎（AD），也称为湿疹，其特征在于过敏性皮肤炎症，伴随免疫细胞（包括T细胞和肥大细胞（MC））的重塑和积聚，但其发病机制仍然知之甚少。顽固性瘙痒是最常见的，与AD患者的生活质量差有关。据报告，儿童和成人的全球流行率不断上升，分别影响至少15%和2-10%的人口。不幸的是，与湿疹相关的残疾负担仍然很高。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，与免疫抑制药物的有害副作用相关，引发了许多正在进行的治疗研究，强调了AD中对更好药理学选择的未满足的医疗需求。由于其炎症组分需要不同分子途径的协调作用，我们推断microRNA，最近被认为是通过mRNA靶向的疾病过程的有效表观遗传调节因子的小的非编码RNA，可以在AD发展过程中观察到的基因和蛋白质表达的时空控制中发挥重要作用。关于AD中发生的这种表观遗传变化知之甚少。此外，尽管80%的AD患者显示高水平的循环免疫球蛋白（IG）E，即在过敏患者中检测到的IG同种型，但AD的过敏成分仍然存在争议。皮肤MC位于血管周围，是过敏反应的关键效应物，在人类和小鼠的AD皮肤病变中数量增加。我们已经发现，过敏原交联MC表达的IgE高亲和力受体（FcεRI）触发MC活化，随后释放与Stat 3转录因子相关的趋化因子，并激活鞘氨醇激酶1（SphK 1），该酶产生鞘氨醇-1-磷酸（S1 P），一种有效的炎症和趋化脂质介质。使用一个完善的AD样小鼠模型，我们已经确定了一组三个miRNA在发炎的皮肤中一致下调，这导致了许多参与MC生物学和免疫细胞募集的靶基因的上调。本申请的目的是：建立AD发病时的miRNA谱及其与MC功能的相关性;阐明由miRNA三联体控制的信号通路及其与S1 P和趋化因子产生和MC活化的相关性。我们预计我们提出的研究将提供证据表明表观遗传学在调节AD启动中的重要性，涉及MC和S1 P通过Stat 3介导的趋化因子产生对炎性细胞募集的贡献，从而导致AD进展。我们提出这些机制的见解将确定新的分子靶点，以防止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.