Mechanisms of age-dependent loss of resistance to allergic contact dermatitis in mice with innate immune system defects

过敏性接触性皮炎（ACD）是一种由蛋白质反应性低分子量化学物质（也称为半抗原）引起的炎症性皮肤病。ACD患病率高且呈稳步上升趋势，是最重要的职业性皮肤病之一。我们之前在小鼠接触性超敏反应（CHS）模型中表明，接触性过敏原触发先天炎症免疫反应，该反应需要IL-12Rb2、TLR2和TLR4以及p2x7r介导的NLRP3炎性体和IL-1b的激活。缺乏TLR2/4、TLR4/IL-12Rb2或P2X7R、NLRP3或IL-1R的小鼠对CHS具有抗性。然而，所有这些小鼠品系在大约18周龄或更大时变得完全易感。这种与年龄相关的对CHS的抵抗力丧失是当前项目的主题。我们的研究重点是分析1)皮肤屏障功能和2)先天炎症和应激反应及其与抗原特异性T细胞反应的关系。根据我们的初步数据，我们的工作假设是：先天信号通路的缺乏扰乱了包括皮肤屏障功能在内的免疫稳态。这导致了低水平的炎症，部分原因是与年龄相关的内脏脂肪组织的增加，最重要的是皮下脂肪组织的增加。因此，对CHS的易感性是后天获得的。这涉及其他促炎途径，如组织应激和损伤反应。该项目将为先天免疫系统、脂肪组织、应激反应之间的关系以及它们在免疫稳态和免疫反应的基因型和年龄依赖性变化中的作用提供新的见解。

Allergic contact dermatitis (ACD) is an inflammatory skin disease that is caused by protein-reactive low molecular weight chemicals, also called haptens. The prevalence of ACD is high and steadily increasing, and it is one of the most important occupation-related skin diseases. We have previously shown in the mouse contact hypersensitivity (CHS) model that contact allergens trigger an innate inflammatory immune response that requires IL-12Rb2, TLR2 and TLR4 as well as the P2X7R-mediated activation of the NLRP3 inflammasome and IL-1b. Mice deficient for TLR2/4, TLR4/IL-12Rb2 or P2X7R, NLRP3 or IL-1R are resistant to CHS. However, all of these mouse strains become fully susceptible at around 18 weeks of age and older. This age-dependent loss of resistance to CHS is the topic of the current project. Our investigations focus on the analysis of 1) the skin barrier function and 2) innate inflammatory and stress responses and their relation to the antigen-specific T cell response. Based on our preliminary data our working hypothesis is: the lack of innate signaling pathways disturbs immune homeostasis including skin barrier function. This leads to low-level inflammation, in part due to age-related increase in visceral and, most importantly, subcutaneous adipose tissue. As a result, susceptibility to CHS is acquired. This involves alternative proinflammatory pathways, e.g. tissue stress and damage responses. This project will provide new insights into the relationship between the innate immune system, adipose tissue, stress responses as well as their role in genotype- and age-dependent changes in immune homeostasis and immune responsiveness.