Lung
P9
Role of neuropilin-1 on lung macrophages during pulmonary inflammation
Principal investigators
Univ.-Prof. Dr. rer. nat.
Johannes Eble
Univ.-Prof. Dr. med.
Summary
Macrophages safeguard the body and organs from unwanted pathogens by attacking them and engulfing them. During an infection of the lung, the macrophages stationed in the lung are strongly reinforced by macrophages that, originated as monocytes from the blood, has immigrated into the lung tissue.
Interestingly, macrophages are among the few cells of the body`s defense and immune system, which express the protein neuropilin-1 on their cell surface. Our previous results have shown, that its presence on monocyte-derived macrophages influences the invasion of pathogen-neutralizing lung macrophages. However, its role and functions on immigrating monocytes and pathogen-attacking macrophages during lung inflammation is rather scarce. As neuropilin-1 lacks any of the molecular moieties, that a cell surface receptor needs for signaling, it usually associated with signaling-competent receptors, such as the receptors for vascular endothelial growth factor (VEGF)-A of hepatocyte growth factor (HGF).
To understand the actions of neuropilin-1 on lung macrophages during pulmonary inflammation, we aim 1) to unravel the neuropilin-1 ligands and co-signaling receptors in the cell membrane of lung macrophages, 2) to study the cellular consequences of different neuropilin-1-ligands on macrophage polarization and function, 3) to analyze the functional impact of Nrp1 on lung macrophages in vivo in mice models during pulmonary inflammation and resolution, and 4) to develop an Nrp1-targeting molecule to improve the life-saving actions of alveolar macrophages in lung inflammation.
Zwischenüberschrift
To accomplish these aims, we will use protein-chemical analyses to examine potential ligands and corresponding co-receptors of neuropilin-1 on lung macrophages on the molecular level. Recombinant neuropilin-1 ligand mimetics will be helpful tools to manipulate macrophage actions, triggered by neuropilin-1 and its co-receptor. On the cellular level, we will study the effect of neuropilin-1 ligands on typical macrophage functions, such as polarization, migration, cytokine secretion, and its underlying signaling mechanism. To translate our findings to a preclinical model, we will apply a murine lung inflammation model, where we will examine the invasion and pathogen-attacking functions of lung macrophages in response to the characterized neuropilin-1 ligands, either the natural ones or recombinant mimetics. With this new knowledge about the role of neuropilin-1 on lung macrophages during pulmorary inflammation, we aim to develop macrophage-selective tools that target neuropilin-1 only on these cells, to improve their function in pathogen defence and lung tissue preservation.
