Mast cells in skin innate immune defense

描述(由申请人提供)：肥大细胞(MC)的多功能本质已经通过它们参与先天性和获得性免疫反应而被揭示。最近对MC各种功能的深入研究表明，这些天然免疫效应器具有杀死微生物和改变经典获得性免疫反应的双重能力。抗菌肽(AMPs)是抗菌素家族的成员，由损伤部位的MC和上皮细胞表达。放线菌素多肽的颗粒定位、细胞外释放及其调节炎症反应的能力表明，放线菌素在MC抵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是皮肤中防御细菌和病毒感染的哨兵。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，而用皮肤MCs重组的KitW-sash-/-小鼠表现出正常的反应。利用长春新素基因缺陷小鼠来源的巨噬细胞，我们发现抗菌肽(AMPs)是关键的抗病原颗粒成分。通过Toll样受体(TLR)-2传递的信号增加了抗菌肽MCs的水平，增强了它们对抗皮肤感染的能力。这一建议的中心假设是，MC通过协调其他细胞反应和表达长春新素多肽，在皮肤对感染的先天免疫反应中发挥重要作用。其中几个实验将侧重于确定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MC在皮肤天然免疫防御中的作用被阐明，Aim 2将研究MC AMPs在皮肤感染过程中的调节和功能。了解MC在皮肤防御外来病原体中的作用将为抗击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.