Non-canonical functions of neutrophils

点击翻译按钮获取中文摘要

Project Summary Tissue function demands the concerted function of specialized parenchymal cells, as well as structural (vascular and mesenchymal) cell. Innate immune cells, such as macrophages that populate and specialize in every organ, are now recognized actors in supporting tissue function and long-term fitness. Only recently, neutrophils, the most abundant innate immune leukocytes, have taken center stage and their functional diversity found important in the context of disease. For example, low density neutrophils in cancer patients are a source of angiogenic and immune-suppressive cues, whereas those that form NETs are a source of autoantigens and chronic inflammation. In contrast to their contributions to disease, we have pioneered studies showing that, like macrophages, neutrophils are part of normal tissue homeostasis and that they can adapt to multiple environments in the healthy organism. These new findings prompt the need to better understand how neutrophils adapt to the different environments to fully grasp their contributions to homeostasis, and to determine the extent to which they are co-opted by different types of disease. This is particularly relevant in the context of acute or chronic inflammation, as perturbations of specific neutrophil fates in organs may compromise tissue fitness, and increase the susceptibility to disease. The overarching goal of this proposal is to understand the mechanisms that shape neutrophil fates in tissues as a first step to define their actual contributions to organismal physiology beyond immune defense. In the long term, we ambition to use this knowledge to build precision medicine based on the remarkable plasticity of these cells. To achieve these goals, we will first focus on the lung as model organ to define how neutrophils naturally acquire angiogenic properties using mouse genetics, and the consequences of disrupting this program in tissue repair (Aim 1). We will then query how neutrophils acquire a surprising matrix-producing signature in barrier tissues, and use biomechanical and imaging tools to define the contribution of this program to barrier integrity and repair in the skin (Aim 2).