Cytokine regulation of skin barrier function

项目总结/摘要 特应性皮炎（AD）是一种慢性复发性皮肤炎性疾病， 免疫系统与皮肤结构细胞的关系Th 2细胞产生的细胞因子至关重要 特应性炎症的促进剂，以及阻断IL-4（Th 2细胞因子之一）的作用的生物治疗剂。 细胞因子在治疗AD中是有效的。从机制上讲，IL-4通过促进 趋化因子的产生允许增加细胞向发炎组织的募集，减少趋化因子的表达。 角质形成细胞中有助于屏障功能的基因，并损害皮肤中的先天病原体防御。我们 通过证明IL-4能够损害再灌注损伤， 创伤后皮肤的上皮形成。在一种由瘙痒-抓挠-创伤循环延续的疾病中， 不能从伤口恢复和恢复屏障功能是慢性疾病的关键组成部分。之间 我们在上一个资助周期中的发现表明，暴露于IL-4的角质形成细胞 使用特应性皮炎模型在体外和体内均损害伤口愈合反应。IL-4刺激 抑制角质形成细胞中的纤连蛋白表达，并向培养物或局部补充纤连蛋白 AD模型中受伤的组织。重要的是，虽然伤口愈合已被广泛研究， 特应性环境改变伤口愈合是完全未知的。在下一个融资期，我们将重新定义- 上皮形成调节回路涉及IL-4、γδ T细胞、角质形成细胞和纤连蛋白。实验 第一个目标将定义有助于改变AD模型中伤口愈合的IL-4应答细胞。 基于AD模型的皮肤中γδ T细胞的急剧损失的初步数据，第二个目的是研究AD模型的皮肤中γδ T细胞的变化。 将决定γδ T细胞对伤口愈合的贡献在特应性环境中如何改变。最终 第三个目标将集中在测试局部纤连蛋白应用在人类皮肤移植模型中的功效。 总之，这些目标中的研究将从机制上定义免疫细胞和结构细胞的相互作用 在特应性环境的背景下，在伤口愈合反应期间， 治疗AD病理的方法。

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.