Project Details
Projekt
The role of interleukin 3 in atherosclerosis
Applicant
Dr. Wolfram Christian Poller, Ph.D.
Subject Area
Cardiology, Angiology
Term
from 2017 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 398190272
Atherosclerosis is a chronic inflammatory disease characterized by the progressive accumulation of lipoproteins and leukocytes in the vessel wall. Erosions or ruptures of atherosclerotic plaques cause fatal events such as myocardial infarction and stroke. Despite important medical progress in health education and drug therapy atherosclerosis remains the leading cause of death worldwide. Thus, there is an urgent need for additional approaches to mitigate this disease. Monocytes and neutrophils are decisive contributors to the pathology of plaque formation and destabilization. However, interfering with the inflammatory generation of leukocytes to treat atherosclerosis is challenging because leukocytes are also critical to host defense. Swirski et al. have recently demonstrated that interleukin 3 (IL-3) is a very powerful inducer of monocyte and neutrophil production controlling IL-1, IL-6, and TNFα release in inflammation, while it is dispensable to the steady state hematopoiesis. This position makes IL-3 an attractive target for novel anti-atherosclerotic therapies that control inflammation but preserve immunity. The proposed research project will test the hypothesis that IL-3 is a master regulator of inflammatory hematopoiesis in atherosclerosis. Therefore, we will profile atherogenesis in IL-3 deficient and IL-3 receptor (CD123) deficient mice on Apoe-/- background. We will identify the cellular source of IL-3 and its duration of expression in atherosclerosis initiation and progression. We will determine the types and numbers of leukocytes that are dependent on IL-3 using flow cytometry of bone marrow, blood, spleen, and aorta. Leukocyte functions will be analyzed by profiling the release of cathelicidins, NETs, cytokines, chemokines, proteases and peroxidases as well as the ability to phagocytose, efferocytose, present antigen, and produce immunoglobulins. Fate mapping and intravital microscopy will be conducted to study the in vivo behavior of leukocytes in the bone marrow niche and to identify how IL-3 influences migration and leukocyte interaction. We will look beyond leukocytes, which is crucial because endothelial cells also express the IL-3 receptor and therefore might be susceptible to IL-3’s function e.g. by promoting leukocyte recruitment. We will determine the effect of IL-3 on lipid metabolism. Plaque evolution, inflammatory status and cell content will be non-invasively monitored using fluorescence molecular tomography (FMT) combined with CT angiography. Histology and molecular pathology are accompanied by gene expression assays to further characterize the effect of IL-3 on atherosclerotic plaque formation. Overall, this project will help to better understand the role of IL-3 in atherosclerosis and test its potential as novel therapeutic target.
DFG Programme
Research Fellowships
International Connection
USA
