Cytokine regulation of skin barrier function

项目摘要/摘要 特应性皮炎(AD)是一种由于相互作用而导致的皮肤慢性复发性炎症状态 免疫系统和皮肤中的结构细胞。Th2细胞产生的细胞因子是至关重要的 特应性炎症的促进剂，以及阻断Th2细胞之一IL-4影响的生物疗法 细胞因子，在治疗AD方面是有效的。从机制上讲，IL-4通过促进 趋化因子的产生增加了细胞对炎症组织的募集，减少了 角质形成细胞中的基因有助于屏障功能，并损害皮肤的天然病原体防御。我们 通过证明IL-4能够损害Re-Re，加深了我们对这一过程的理解。 创伤后皮肤上皮化。在一种通过瘙痒-抓挠-伤口循环而永久存在的疾病中， 无法从伤口中恢复和恢复屏障功能是慢性病的一个关键组成部分。其中 在我们之前的资金周期中的发现表明，暴露于IL-4的角质形成细胞具有 使用特应性皮炎模型在体外和体内都损害了伤口愈合反应。IL-4刺激 抑制角质形成细胞中纤维连接蛋白的表达，并在培养中或局部补充纤维连接蛋白 对AD模型中损伤组织的影响。重要的是，虽然伤口愈合已经被广泛研究，但 特应性环境改变伤口愈合是完全未知的。在下一个资助期，我们将重新定义- 涉及IL-4、γδT细胞、角质形成细胞和纤维连接蛋白的上皮化调节回路。实验在 第一个目标将定义在AD模型中有助于改变伤口愈合的IL-4反应细胞。 基于AD模型皮肤中γδT细胞显著丢失的初步数据，第二个目的是 将决定在特应性环境中γδT细胞对伤口愈合的贡献是如何改变的。决赛 第三个目标将集中于测试局部应用纤维连接蛋白在人类皮肤移植模型中的效果。 总之，这些目标的研究将从机械上定义免疫细胞和结构细胞之间的相互作用 在特应性环境中的伤口愈合反应期间，并将测试潜在的新的 阿尔茨海默病的病理治疗方法。

PROJECT SUMMARY/ABSTRACT Atopic dermatitis (AD) is a chronic relapsing inflammatory condition of the skin that results from the interactions of the immune system with the structural cells in the skin. Cytokines produced by Th2 cells are critical promoters of atopic inflammation, and biological therapeutics that block the effects of IL-4, one of the Th2 cytokines, are efficacious in treatment of AD. Mechanistically, IL-4 potentiates inflammation by promoting chemokine production allowing increased recruitment of cells to the inflamed tissue, decreases expression of genes in keratinocytes that contribute to barrier function, and impairs innate pathogen defenses in the skin. We have added to our understanding of this process by demonstrating the ability of IL-4 to impair re- epithelialization of the skin after wounding. In a disease that is perpetuated by an itch-scratch-wound cycle, the inability to recover from wounds and restore barrier function is a critical component of chronic disease. Among the discoveries in our previous cycle of funding we demonstrated that keratinocytes exposed to IL-4 have impaired wound-healing responses both in vitro and in vivo using a model of atopic dermatitis. IL-4 stimulation repressed fibronectin expression in keratinocytes, and supplementing fibronectin either to cultures, or topically to wounded tissue in models of AD. Importantly, while wound healing has been studied extensively, how the atopic environment alters wound healing is completely unknown. In the next funding period we will define a re- epithelialization regulatory circuit that involves IL-4, γδ T cells, keratinocytes, and fibronectin. Experiments in the First Aim will define the IL-4-responsive cells that contribute to altered wound healing in models of AD. Based on preliminary data that there is a dramatic loss of γδ T cells in the skin of AD models, the Second Aim will determine how the γδ T cell contribution to wound healing is altered in an atopic environment. The final Third Aim will focus on testing the efficacy of topical fibronectin application in human skin transplant models. Together, the studies in these Aims will mechanistically define the interactions of immune and structural cells during a wound healing response in the context of an atopic environment, and will test potential new approaches to treating the pathology in AD.