Regulators of type 2 immunity in tissue regeneration

组织再生中 2 型免疫的调节因子

• 批准号: 392749992
• 负责人: Professorin Dr. Sabine Eming
• 金额: --
• 依托单位: Klinik für Dermatologie und Venerologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/392749992?language=en
• 关键词: Regulators; type; immunity; tissue; regeneration

Tissue injury induces a complex, dynamic cellular program proceeding in sequential phases of inflammation, followed by tissue growth and differentiation. Depending on the tissue’s regenerative capacity and quality of the inflammatory response, the outcome is generally imperfect with some degree of fibrosis. Myeloid cells are an essential component of the body’s innate ability to restore tissue function after injury by facilitating wound debridement and by producing chemokines and growth factors. If this well-orchestrated response becomes dysregulated, it may cause a chronic wound or progressively mount a fibrotic response with both outcomes impairing tissue function that can ultimately lead to organ failure and death. In recent studies we were able to link phase specific monocyte/macrophage activation phenotypes to specific repair responses in different models of acute and chronic skin injury. Our findings suggest that polarization dynamics of wound macrophages are critical to instruct tissue resident cells to initiate the cutaneous healing response, but also to coordinate differentiation and termination signals. Whereas early stage wound macrophages reflect a type-1 immune response, late stage wound macrophages are characterized by a type-2 immune response. Specifically, during maturation of the healing response we identified IL-4Rα-signaling in late stage wound macrophages as critical regulator of collagen fibril assembly and ECM function. Currently it is unresolved how signalling pathways and transcriptional networks in monocytes/macrophages coordinate their functional plasticity during the sequential repair stages. The overall goal of this project is to identify regulators and effectors of the type 2 immune response in skin regenerative processes. Specifically, we aim to identify the spatiotemporal distribution of different cellular sources of IL-4 and IL-13 in models of acute and chronic skin injury and repair. Further, we will dissect the crosstalk between white adipose tissue (WAT) and macrophage polarization and its functional consequences in different conditions of physiological or pathological repair responses in the skin. In addition, we investigate direct effects of type 2 cytokine signaling in adipocytes and its implication for skin homeostasis and repair. To address these questions we will use a combination of biochemical, molecular and morphological analytical methodologies in gene modified mouse models as well as transcriptome analysis. Collectively, we propose that these analyses provide a comprehensive and systematic approach to deliver new mechanistic insights into how type 2 cytokines mediate tissue protective functions in skin maintenance, damage and repair.

组织损伤诱导在炎症的连续阶段中进行的复杂的动态细胞程序，随后是组织生长和分化。根据组织的再生能力和炎症反应的质量，结果通常是不完美的，具有一定程度的纤维化。骨髓细胞是机体在损伤后通过促进伤口清创和通过产生趋化因子和生长因子来恢复组织功能的先天能力的重要组成部分。如果这种精心策划的反应变得失调，它可能会导致慢性伤口或渐进性纤维化反应，这两种结果都会损害组织功能，最终导致器官衰竭和死亡。在最近的研究中，我们能够在急性和慢性皮肤损伤的不同模型中将时相特异性单核细胞/巨噬细胞活化表型与特异性修复反应联系起来。我们的研究结果表明，伤口巨噬细胞的极化动力学是至关重要的，以指导组织驻留细胞启动皮肤愈合反应，但也协调分化和终止信号。早期伤口巨噬细胞反映1型免疫应答，而晚期伤口巨噬细胞的特征在于2型免疫应答。具体而言，在愈合反应的成熟过程中，我们确定了晚期伤口巨噬细胞中的IL-4 R α信号传导是胶原纤维组装和ECM功能的关键调节剂。目前，它是未解决的信号通路和转录网络在单核细胞/巨噬细胞协调其功能可塑性在顺序修复阶段。该项目的总体目标是确定皮肤再生过程中2型免疫反应的调节因子和效应因子。具体来说，我们的目标是确定急性和慢性皮肤损伤和修复模型中不同细胞来源的IL-4和IL-13的时空分布。此外，我们将剖析白色脂肪组织（WAT）和巨噬细胞极化之间的串扰及其在皮肤中的生理或病理修复反应的不同条件下的功能后果。此外，我们研究了2型细胞因子信号在脂肪细胞中的直接作用及其对皮肤稳态和修复的影响。为了解决这些问题，我们将在基因修饰的小鼠模型以及转录组分析中使用生物化学，分子和形态学分析方法的组合。总的来说，我们建议这些分析提供了一个全面和系统的方法，提供新的机制的见解2型细胞因子如何介导皮肤维护，损伤和修复的组织保护功能。