Regulators of type 2 immunity in tissue regeneration

组织损伤诱导了一个复杂的、动态的细胞程序，在炎症的顺序阶段进行，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，并伴有一定程度的纤维化。髓系细胞是机体先天修复损伤后组织功能的重要组成部分，它能促进伤口清创，产生趋化因子和生长因子。如果这种精心安排的反应变得失调，可能会导致慢性伤口或逐渐形成纤维化反应，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，我们能够将不同急性和慢性皮肤损伤模型中特异性单核细胞/巨噬细胞激活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对于指导组织驻留细胞启动皮肤愈合反应至关重要，但也协调分化和终止信号。早期伤口巨噬细胞反映1型免疫反应，而晚期伤口巨噬细胞表现为2型免疫反应。具体来说，在愈合反应成熟过程中，我们发现晚期伤口巨噬细胞中的il - 4r α-信号是胶原原纤维组装和ECM功能的关键调节因子。目前，单核/巨噬细胞的信号通路和转录网络如何在顺序修复阶段协调其功能可塑性尚不清楚。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，我们的目的是确定不同细胞来源的IL-4和IL-13在急性和慢性皮肤损伤和修复模型中的时空分布。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音及其在皮肤生理或病理修复反应的不同条件下的功能后果。此外，我们还研究了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，我们将在基因修饰小鼠模型以及转录组分析中使用生化，分子和形态学分析方法的组合。总之，我们提出这些分析提供了一种全面和系统的方法，为2型细胞因子如何介导皮肤维护、损伤和修复中的组织保护功能提供了新的机制见解。

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.