The uncharted journeys of inflammatory cells and their functional implications

炎症是对伤害或有害物质的生理反应，以确保组织防御入侵的微生物。这是通过炎症细胞，如中性粒细胞和巨噬细胞（也称为“骨髓细胞”）来实现的，它们迅速迁移到受损的位点，并执行关键的抗菌和组织修复功能。然而，过度或适应性不良的炎症与一系列疾病有关，从自身免疫到癌症和神经变性。靶向炎症的一个关键问题是我们对骨髓细胞在体内的迁移模式的有限理解。研究的重点是这些细胞如何到达炎症位点，而对它们的长期命运知之甚少。理解这一点很重要，因为越来越多的证据表明，骨髓细胞从炎症病变扩散到其他组织，这对炎症和宿主防御的解决具有重要意义。在这里，我们建议结合体内成像，遗传操作和单细胞转录组学在一个可驯化的脊椎动物（斑马鱼）中，阐明髓细胞播散的机制，定义播散细胞的身份及其功能意义。首先，我们将通过实时成像和细胞追踪确定中性粒细胞和巨噬细胞在遇到微生物后的迁移路线，并通过遗传扰动确定潜在的分子机制。其次，我们将通过单细胞转录组学来确定传播炎症细胞的特性，这将为本研究提供功能和机制假设，并揭示用于检测体内炎症状态的新生物标志物。最后，我们将通过追踪单个细胞从一次感染到下一次感染的行为来阐明这些细胞在免疫监视中的功能。这项工作将填补关于炎症反应如何在体内展开的主要知识空白，并形成操纵炎症以提高分辨率或宿主防御的新思路。

Inflammation is a physiological response to injury or harmful agents that ensures tissue defence from invading microbes. This is achieved through inflammatory cells, such as neutrophils and macrophages (also called 'myeloid cells'), which rapidly migrate to damaged loci and execute crucial antimicrobial and tissue repair functions. However, excess or maladaptive inflammation is linked to a range of diseases, from autoimmunity to cancer and neurodegeneration. A key problem in targeting inflammation is our limited understanding of the migration patterns of myeloid cells in vivo. Studies have focused on how these cells reach inflammatory loci, while little is known about their long-term fates. This is important to understand, as increasing evidence reveals that myeloid cells disseminate to other tissues from inflamed lesions, which has implications in resolution of inflammation and host defence.Here, we propose to combine in vivo imaging, genetic manipulations and single-cell transcriptomics in a tractable vertebrate (zebrafish), to elucidate the mechanisms of myeloid cell dissemination, define the identity of disseminating cells and their functional implications. First, we will determine the migration routes of neutrophils and macrophages after microbial encounter, through live imaging and cell tracing, and define the underlying molecular mechanisms, through genetic perturbations. Secondly, we will determine the properties of disseminating inflammatory cells, through single cell transcriptomics, which will generate functional and mechanistic hypotheses for this study and reveal new biomarkers for detection of in vivo inflammatory states. Finally, we will elucidate functions of these cells in immunosurveillance, by tracing the behaviour of individual cells from one infection to the next.This work will fill a major knowledge gap on how inflammatory responses unfold in vivo and shape new ideas for manipulating inflammation towards improved resolution or host defence.