Mast cells in skin innate immune defense

摘要 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反应。最近对 MC的各种功能表明，这些先天免疫效应子具有 具有杀死微生物和改变经典适应性免疫反应的双重能力。 抗菌肽（AMP）的凯萨林菌素家族的成员由以下表达： 损伤部位的MC和上皮细胞。抗菌肽的颗粒定位 肽，它们的细胞外释放，以及它们调节炎症反应的能力 表明cathelicidin在MC对抗皮肤的能力中起着重要作用， 感染初步数据显示，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（KitW-sash-/-）小鼠 比野生型小鼠更容易受到皮肤感染，而KitW-/-小鼠 用皮肤MC重建的细胞显示正常反应。使用来自小鼠的MC 缺乏cathelicidin，我们发现抗菌肽（AMP）是关键的抗- 致病颗粒成分。通过Toll样受体（TLR）-2的信号传导增加 抗微生物肽MCs的水平，增强其对抗皮肤感染的能力。 该建议的中心假设是，MCs在皮肤中起着重要作用 通过协调其他细胞反应对感染的先天免疫反应， 表达cathelicidin肽。几个实验将集中在建立 MCs如何改变皮肤微环境并与其他细胞协调以响应 感染（目标1）。一旦MCs在皮肤先天免疫防御中的作用被证实， 阐明，目的2将检查皮肤过程中MC AMP的调节和功能 感染.了解MCs在皮肤防御外来病原体中的作用， 提出了对抗感染的新的治疗靶点。

Abstract 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.