Regulators of type 2 immunity in tissue regeneration

组织损伤导致一个复杂的、动态的细胞程序，在炎症的连续阶段进行，随后是组织的生长和分化。取决于组织的再生能力和炎症反应的质量，结果通常是不完美的，并有一定程度的纤维化。髓系细胞是人体在受伤后通过促进伤口清创以及产生趋化因子和生长因子来恢复组织功能的与生俱来的能力的重要组成部分。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，最终可能导致器官衰竭和死亡。在最近的研究中，我们能够在不同的急性和慢性皮肤损伤模型中将时相特异性单核/巨噬细胞激活表型与特异性修复反应联系起来。我们的发现表明，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，也是协调分化和终止信号的关键。早期伤口巨噬细胞反映的是1型免疫反应，而晚期伤口巨噬细胞的特征是2型免疫反应。具体地说，在愈合反应的成熟过程中，我们发现晚期伤口巨噬细胞中的IL-4Rα信号是胶原纤维组装和细胞外基质功能的关键调节因子。目前，单核/巨噬细胞中的信号通路和转录网络如何协调其在顺序修复阶段的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型免疫反应的调节器和效应器。具体地说，我们的目标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扰及其在皮肤不同生理或病理修复反应条件下的功能后果。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动态平衡和修复的影响。为了解决这些问题，我们将在基因修饰的小鼠模型中结合使用生化、分子和形态分析方法以及转录组分析。总而言之，我们认为这些分析提供了一种全面和系统的方法，以提供关于2型细胞因子如何在皮肤维护、损伤和修复中介导组织保护功能的新的机械性见解。

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.