Neutrophils sense and respond to various types of signals generated within tissues. Such signalling occurs during steady state or inflammation and affects production as well as function of peripheral neutrophils. As an example, neutrophils contributing to tissue repair in the liver re-enter the circulation, take a sojourn in the lungs where they are reprogrammed to up-regulate CXCR4 thus rendered prone to clearance in the bone marrow. Similarly, during low dose endotoxinaemia, instructed lung neutrophils locally change their chemokine receptor profile and release neutrophil extracellular traps (NETs). A recent study revealed the plasticity of neutrophils within tissues during steady state, thus enabling neutrophils to acquire different functional states depending on tissue cues. These are just three examples of how the local microenvironment can shape neutrophil phenotype and function. However, the importance of the microenvironment can be extended to metabolic alterations including hyperlipidaemia and hyperglycaemia, as well as to inflammation and cancer. In project area A, several projects aim at studying the importance of extracellular signals derived from the environment for neutrophil production and function.
A1: Organ-specific priming during granulopoiesis generates neutrophil subsets (Carlos Silvestre-Roig)
Neutrophils are traditionally been looked upon as a homogenous population of short-lived, end-differentiated, and transcriptionally silent leukocytes. In this project, we will develop a concept of neutrophil heterogeneity based on the organ-dependent specification of neutrophil progenitors to differentiate into distinct neutrophil lineages. Multi-omics analyses and functional studies will reveal the contribution of splenic and bone marrow neutrophils to regulation of the immune response and tissue damage during inflammation.
A2: Neutrophil education in peripheral vascular beds (Oliver Soehnlein)
The aim of the present proposal is to unravel the importance of the vascular periphery – over and above processes occurring in the bone marrow – as site of end-stage neutrophil maturation. Given tremendous proteomic and transcriptomic difference in mature bone marrow and circulating neutrophils, we hypothesize that neutrophils undergo final stages of maturation in the periphery. Successfully addressing these aims would provide an innovative paradigm to understanding neutrophil biology as it will establish peripheral vascular beds as a novel (possibly disease generating) component during neutrophil maturation.
A3: Identification of a molecular signature that influences neutrophil migration and function in urinary tract infection during chronic lymphocytic leukaemia (Daniel Engel)
Neutrophils are very important leukocytes for the acute control of urinary tract infection (UTI). However, patients that suffer from chronic lymphocytic leukaemia (CLL) are highly susceptible to bacterial infection, such as UTI. Here, we will use models that combine CLL and UTI and will evaluate molecules that affect neutrophil migration and function and predispose to severe bacterial infections in CLL.
A4: Deciphering molecular links between the tumour microenvironment and functional plasticity of tumour-associated neutrophils (Sven Brandau)
A high intratumoural frequency of neutrophils (designated TAN) is associated with poor outcome in cancer patients. This project aims to identify the distinct mechanisms that regulate TAN recruitment and density in the tumour core and the tumour stroma. To this end, we will map the human tumour microenvironment by spatial omics analyses, relate this information with neutrophil counts and phenotype, and validate identified candidate molecules using in vitro and in vivo models. Thus, this project will identify clinically relevant factors that help to explain the well-documented tumour promoting function of TAN in the human oncology space.
A5: Impact of type I interferons on tumour-dependent granulopoiesis and neutrophil tumourigenicity (Anja Hasenberg & Jadwiga Jablonska)
The aim of this proposal is to unravel the role of IFN receptor (IFNAR1) in the development of tumour-associated neutrophils. As lack of IFNAR1 leads to pro-tumour activity of neutrophils and as IFNAR1 expression is significantly downregulated in the tumour microenvironment, we hypothesize that the tumour actively disturbs IFNAR1 signalling to support the development of pro-tumour neutrophils. Bearing this in mind, we aim to identify the molecular mechanisms involved in the development of neutrophils in IFNAR1 deficiency, thus potentially identifying novel therapeutic targets that allow to reverse the pro-tumour bias of neutrophils.
A6: Macrophage regulation of neutrophil phenotype and function (Christian Schulz)
Neutrophils are potent effector cells and therefore require precise regulation. Within organs, they quickly adopt tissue-dependent properties to serve specific physiological needs. Because neutrophils and macrophages frequently interact, we hypothesize that tissue-resident macrophages modulate neutrophil properties. Here, we will determine the impact of tissue macrophages on neutrophil phenotypes and functions, and characterize the potential role of the developmental origin of macrophages therein. Further, we will analyse the importance of macrophages for shaping neutrophil properties in a model of cardiac injury.
A7: Soluble and crystalline metabolites as modulators of neutrophil function (Hans-Joachim Anders & Stefanie Steiger)
Soluble and crystalline metabolites have immunomodulatory effects on immune cells that affect various forms of sterile inflammation especially when kidney failure impairs metabolite excretion. The overarching aim of this proposal is to investigate the molecular mechanisms of how soluble and crystalline metabolites (uric acid, oxalate and cholesterol) impact on neutrophil functions including phagocytosis, migration, and NET release, hence yielding insights with potential therapeutic relevance.