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Autonomic nervous regulation of the macrophage response in infarct healing

Subject Area Cardiology, Angiology
Term from 2019 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 411719800
 
Final Report Year 2023

Final Report Abstract

My research dealt with the role of innate immunity in cardiovascular diseases with a special focus on the regulation of hematopoiesis during myocardial infarction (MI) and atherosclerosis. The fellowship resulted in the publication of several first-author articles (mostly in a joint effort with my colleagues) which elucidate different aspects of the aforementioned topic. In one research project, we investigated how newly designed nanoparticles encapsulating small interfering RNA can regulate the release of hematopoietic stem cells from the bone marrow and improve infarct healing. In another project, we showed that serial MI leads to a memory effect in the bone marrow niche which dampens the hematopoietic response to subsequent MIs. A further study developed a new mouse model of sepsis-induced atrial fibrillation which can be widely used to research arrhythmia and inflammation in mice. The main research project of my postdoc studied the way in which acetylcholine-producing B lymphocytes in the bone marrow regulate hematopoiesis at steady state and during cardiovascular diseases. It is well known that sympathetic fibers secrete noradrenalin in the marrow which alters hematopoietic factors leading to increased stem cell proliferation. Whether the parasympathetic branch exerts similar effects on the bone marrow niche remains unknown. In this project, we confirmed the absence of vagal nerves in the trabecular bone (the location of the hematopoietic niche) and instead found acetylcholine producing Chat+ B lymphocytes (both in mice and in humans) and very few Chat+ CD4+ T lymphocytes. Cd19CreChatfl/fl mice (in which choline acetyltransferase, essential for producing acetylcholine, was conditionally deleted in B cells) had significantly lower levels of acetylcholine in the marrow confirming that Chat+ B cells are the main source of bone marrow acetylcholine. Furthermore, Cd19CreChatfl/fl mice were found to have lower levels of retention factors Angpt1 and CXCL12 within niche cells leading to increased hematopoietic stem cell numbers and proliferation. Using single cell RNA sequencing, we screened the bone marrow niche for the acetylcholine receptor Chrna7 and found that endothelial cells, mesenchymal stromal cells, pericytes and nerve-like-cells expressed Chrna7 within the niche. To investigate the function of Chrna7 in niche cells, we bred NestincreChrna7fl/fl mice and found once again enhanced hematopoietic stem cell numbers and proliferation in the marrow. Next, we addressed the questions whether B cell-derived acetylcholine could exert protective functions during emergency hematopoiesis. Cd19CreChatfl/fl mice subjected to MI revealed enhanced myelopoiesis resulting in exaggerated leukocytosis and worsened cardiac function. Similarly, atherosclerotic Cd19CreChatfl/fl mice displayed increased numbers of hematopoietic progenitor cells leading to monocytosis and larger atherosclerotic lesions. Lastly, patients who were on acetylcholinesterase treatment (a medication to increase systemic acetylcholine levels) were found to have lower white blood cell counts at baseline and after MI. In summary, this study shows for the first time that acetylcholine producing Chat+ B lymphocytes stand in for vagal nerves in the bone marrow niche and curtail hematopoiesis both in steady state and during cardiovascular diseases. One may speculate from an evolutionary point of view that the inherent migratory capabilities of B cells allow them to accumulate more flexibly in locations of high demand as compared to nerves. The study’s findings pave the way for potential future immunotherapies targeting the acetylcholine-Chrna7 axis with clinical relevance for a multitude of disease conditions including hematopoietic and inflammatory diseases.

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