Mast cells in skin innate immune defense

描述（由申请人提供）：肥大细胞（MC）的多功能性质已通过其参与先天性和适应性免疫应答而被揭示。最近对MC的各种功能的了解表明，这些先天免疫效应子具有杀死微生物和改变经典适应性免疫应答的双重能力。抗菌肽（AMP）的凯萨林菌素家族的成员由损伤部位的MC和上皮细胞表达。cathelicidin肽的颗粒定位、它们的细胞外释放和它们改变炎症反应的能力表明，cathelicidin在MC对抗皮肤感染的能力中起重要作用。该提案中的初步数据显示，MC是皮肤中的哨兵，用于防御细菌和病毒感染。肥大细胞缺陷型（KitW-sash-/-）小鼠比野生型小鼠更容易受到皮肤感染，而用皮肤MC重建的KitW-sash-/-小鼠显示出正常反应。利用来自缺乏凯萨林菌素的小鼠的MC，我们表明抗菌肽（AMP）是抗病原颗粒的关键组分。通过Toll样受体（TLR）-2的信号传导增加了抗菌肽MCs的水平，增强了它们对抗皮肤感染的能力。 该提议的中心假设是，MC通过协调其他细胞应答和表达凯萨林菌素肽在皮肤对感染的先天免疫应答中发挥重要作用。几个实验将集中在确定MC如何改变皮肤微环境并与其他细胞协调以应对感染（目标1）。一旦阐明了MC在皮肤先天免疫防御中的作用，目标2将研究MC AMP在皮肤感染过程中的调节和功能。了解MCs在皮肤防御外来病原体中的作用将为对抗感染提供新的治疗靶点。

DESCRIPTION (provided by applicant): The multifunctional nature of mast cells (MCs) has been revealed through their involvement in both innate and adaptive immune responses. Recent insight into the various functions of MCs has shown that these innate immune effectors possess the dual ability to kill microbes and to modify classical adaptive immune responses. Members of the cathelicidin family of antimicrobial peptides (AMPs) are expressed by MCs and epithelial cells at sites of injury. The granular localization of the cathelicidin peptides, their extracellular release, and their capacity to modify inflammatory responses suggests that cathelicidin plays an important role in the capacity of MCs to combat skin infection. Preliminary data inside this proposal show that MCs are sentinels in the skin for defending against bacterial and viral infections. Mast cell-deficient (KitW-sash-/-) mice are more susceptible to skin infection than the wild-type mice, while KitW-sash-/- mice reconstituted with skin MCs show a normal response. Using MCs derived from mice deficient in cathelicidin, we showed that antimicrobial peptides (AMPs) are critical anti- pathogenic granule components. Signaling through toll-like receptor (TLR)-2 increased the level of antimicrobial peptide MCs, enhancing their capacity to fight skin infections. The central hypothesis of this proposal is that MCs play a seminal role in the skin innate immune response to infections by orchestrating other cell responses and expressing cathelicidin peptides. Several of the experiments will focus on establishing how MCs modify skin microenvironment and coordinate with other cells to respond to infection (Aim 1). Once the contribution of MCs in skin innate immune defense has been elucidated, Aim 2 will examine the regulation and function of MC AMPs during skin infections. Understanding the role of MCs in skin defense against foreign pathogens will suggest new therapeutic targets for combating infection.