Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells
Frodermann, Vanessa; Rohde, David; Courties, Gabriel; Severe, Nicolas; Schloss, Maximilian J.; Amatullah, Hajera; McAlpine, Cameron S.; Cremer, Sebastian; Hoyer, Friedrich F.; Ji, Fei; van Koeverden, Ian D.; Herisson, Fanny; Honold, Lisa; Masson, Gustavo Santos; Zhang, Shuang; Grune, Jana; Iwamoto, Yoshiko; Schmidt, Stephen P.; Wojtkiewicz, Gregory R.; Lee, I. Hsiu; Gustafsson, Karin; Pasterkamp, Gerard; de Jager, Saskia C.A.; Sadreyev, Ruslan I.; MacFadyen, Jean; Libby, Peter; Ridker, Paul; Scadden, David T.; Naxerova, Kamila; Jeffrey, Kate L.; Swirski, Filip K.; Nahrendorf, Matthias
(2019) Nature Medicine, volume 25, issue 11, pp. 1761 - 1771
(Article)
Abstract
A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically,
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exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin’s effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.
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Keywords: General Biochemistry,Genetics and Molecular Biology
ISSN: 1078-8956
Publisher: Nature Publishing Group
Note: Funding Information: We thank M. Handley, E. Surette and A. Galvin of the HSCI-CRM Flow Cytometry Core Facility, Massachusetts General Hospital, for assistance with cell sorting, the Center for Skeletal Research Imaging and Biomechanical Testing Core (National Institutes of Health P30 AR066261), Massachusetts General Hospital, for bone histology and µCT imaging, the Bioanalytics Core at the Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, University of Louisville, for mass spectrometry analysis, the BPF Next-Gen Sequencing Core Facility at Harvard Medical School for their support for RNA-sequencing and K. Joyes for editing the manuscript. This work was funded in part by federal funds from the National Institutes of Health (HL142494, HL139598, HL131478, HL128264, AI07087, DK040561 and T32HL076136), the European Union’s Horizon 2020 research and innovation program (grant agreement no. 667837), the Deutsche Forschungsgemeinschaft (CR 603/1-1, HO 5279/1-2 and RO 5071/1-1) and a fellowship from the Netherlands Organisation for Scientific Research (Rubicon Grant: 835.15.014). We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
(Peer reviewed)