The influence of regular physical activity on leukocyte production

• Applicant: Maximilian Nickenig
• Subject Area: Cardiology, Angiology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554367378

Cardiovascular disease (CVD) belongs to the leading cause of death world-wide. Successfully modulating cardiovascular inflammation and the immune system could advance treatment and ultimately outcome of CVD, as it has for cancer and inflammatory diseases. Such therapies will have to ameliorate systemic cardio-vascular inflammation while sparing the defense functions of the immune system. One approach to discovering pathways that have such desired profile is to mirror favorable environmental and behavioral strategies. Therefore, this proposal will be studying in detail how physical activity reduces inflammation in atherosclerosis and thereby improves outcome of cardiovascular disease. Regular exercise drastically reduces CVD while physical inactivity is a strong CVD risk factor; accordingly, guidelines recommend at least 150 min of physical activity per week. Exercise protection against CVD is thought to act via reducing hypercholesteremia, obesity and blood pressure. However, some forms of exercise may also attenuate inflammation. Preliminary data shows that voluntarily running mice have less atherosclerosis inflammation due to reduced systemic supply of leukocytes; however, this did not compromise host defense against bacteria2. Physical activity also has strong inverse clinical associations with both leukocytosis and CVD endpoints. This application proposes to study how regular exercise reduces hematopoietic output of inflammatory, CVD-promoting leukocytes. To approach this question without bias, transcriptomics on hematopoietic stem and progenitor cells (HSPC) as well as bone marrow niche cells that regulate HSPC proliferation and lineage bias were performed. Both experiments revealed a distinct metabolic signature of voluntary running. These two independent experiments converged on increased fatty acid oxidation (FAO) and mitochondrial metabolism in the more quiescent HSPC of running mice. These preliminary data led to the overarching hypothesis: voluntary running reprograms the hematopoietic stem cell niche, which induces HSPC quiescence via increased FAO which in turn may impact development of atherosclerosis. This proposed work will take the next steps and tackle the impact of exercise on hematopoiesis from two sides. Aim 1 will test the hypothesis that the contributions of stromal bone marrow cells lead to decreased hematopoiesis during physical activity. Aim 2 will test the hypothesis that exercise-heightened FAO in HSPC lowers systemic inflammation in mice with atherosclerosis. In both aims, cell-specific gene deletion will be used to interrupt metabolic pathways that are regulated by physical activity and potentially influence hematopoiesis. This application aims to reveal how exercise can protect against CVD and how HSPC fatty acid metabolism affects atherosclerotic plaque inflammation. Such information may become a possible foundation for beneficial immunomodulation in CVD patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Matthias Nahrendorf