The Microbiome Drives Mast Cell Recruitment in the Skin

描述（由申请人提供）：目前的文献支持肥大细胞（MCs）在对抗感染中发挥相关作用的概念，我们最近发表的数据证实了肥大细胞在对抗病毒性病原体中发挥重要作用。尽管肥大细胞在先天免疫和获得性免疫中很重要，但肥大细胞的发育和向皮肤的迁移尚不清楚。我们的研究结果表明，皮肤微生物组对MCs迁移到皮肤有很强的影响。我们的初步数据提供了证据，表明皮肤表面细菌产物的存在参与了MC抗菌功能的调节，驱使它们进入皮肤，并协同帮助它们对生存生长因子（SCF）做出反应。我们假设TLR2微生物组产物在皮肤外部界面的MC募集中具有独特的作用，并定义了指导肥大细胞运输和抗菌成熟的环境。在目标1中，我们将定义皮肤微生物组与体内MC先天免疫反应之间的相互作用，并与人类药理学相关。在Aim 2中，我们将分析控制皮肤微生物组释放的TLR2信号与MC先天免疫应答之间串扰的分子机制，并直接应用于人类MC。在Aim 3中，我们将确定TLR2激活对SCF反应和MC成熟的影响，并与MC抗菌功能直接相关。在这些研究的结论中，我们将扩展我们对MC功能和募集的重要新方面的知识，评估肥大细胞和共生菌之间相互作用的新体内模型，确定改善这些相互作用的候选策略，并开发新的工具继续研究MC疾病的发病机制。更具体地说，这项工作对对抗感染、牛皮癣和特应性皮炎（湿疹）有意义，对哮喘和花粉热有长期意义。

DESCRIPTION (provided by applicant): Current literature supports the concept that mast cells (MCs) play a relevant role in fighting infections in general, and our recently published data confirms that MCs play an important role in fighting viral pathogens. Despite their importance in innate and acquired immunity, mast cell development and migration into the skin is not well understood. Our findings suggest that the skin microbiome has a strong influence on migrating MCs into the skin. Our preliminary data provide evidence that the presence of bacterial products at the skin surface participates in the regulation of MC antimicrobial functions, driving them to the skin, and synergistically helping them respond to their survival growth factor, SCF. We hypothesize that TLR2 microbiome products have a unique role in MC recruitment at the outside skin interface and define the environment that directs mast cell trafficking and antimicrobial maturation. In Aim 1 we will define the interactions between the skin microbiome and MC innate immune responses in-vivo, with relevance for human pharmacology. In Aim 2 we will analyze molecular mechanisms governing the crosstalk between TLR2 signals released by the skin microbiome and MC innate immune responses, with direct application to human MCs. In Aim 3 we will determine the impact of TLR2 activation on the SCF response and MC maturation with direct correlation of MC antimicrobial functions. At the conclusion of these studies, we will have expanded our knowledge of important new aspects of MC functions and recruitment, evaluated new in-vivo models of interaction between Mast Cells and Commensal bacteria, identified candidate strategies to improve these interactions, and developed new tools for continued investigation into the pathogenesis of MC disorders. More specifically, this work has implications for fighting infections, psoriasis, and atopic dermatitis (eczema), with longer term significance fr asthma and hay fever.