Regulators of type 2 immunity in tissue regeneration

点击翻译按钮获取中文摘要

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.