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Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells
Open accessAbstract
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, 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-creER T2; Lepr fl/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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“Instead, PA reinforces cardiorespiratory fitness, 31 inhibits inflammatory responses, 32 and improves glucose metabolism.33”
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Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases
Trinh, T. L. P., & Broxmeyer, H. E. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10132-y · Cited by 46
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The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis
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“Exercise seems to modulate two different mechanisms that control circulating leukocyte numbers: acutely, exercise affects leukocyte migration to and from the bone marrow, whereas chronically, exercise alters leukocyte production in the bone marrow 134 .”
InfluentialBone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities
Mitroulis, I., Hajishengallis, G., & Chavakis, T. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad003 · Cited by 42
“55 Exercise in mice has been demonstrated to promote HSPC repopulation potential and lineage output, which lasted for several weeks.”
BackgroundInfluentialCrosstalk between bone and the immune system
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“Exercise-induced reduction of leptin production in adipose tissue promoted CXCL12 expression in LepR + mesenchymal stem cells in the bone marrow, keeping HSCs in a quiescent phase [85].”
BackgroundIntrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise
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“The rapid development of singlecell RNA sequencing (scRNA-seq) technology and the refinement of cytometry allow for elucidation of the responses of the bone microenvironment, including hematopoietic cells and immune cells, to mechanical stimulation [19].”
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“In this manner, the cardiovascular damage was relieved by lessening the inflammatory process [87].”
BackgroundNeuroimmune interactions in cardiovascular diseases
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Matrix biophysical cues direct mesenchymal stromal cell functions in immunity
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Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity
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“Finally, using a murine model of voluntary exercise, Frodermann and colleagues showed that, by diminishing plasma levels of the hormone leptin, exercise reduced HSPC proliferation and lineage commitment, resulting in fewer circulating leukocytes (39).”
MethodBeyond cardiomyocytes: Cellular diversity in the heart's response to exercise
Trager, L. E., Lyons, M., Kuznetsov, A., Sheffield, C., Roh, K., Freeman, R., Rhee, J., Guseh, J. S., Li, H., & Rosenzweig, A. (2022) · Journal of sport and health science/Journal of Sport and Health Science · doi:10.1016/j.jshs.2022.12.011 · Cited by 35
Cardiac macrophage metabolism in health and disease
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Sports and Immunity, from the recreational to the elite athlete
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Trained Immunity and Cardiometabolic Disease
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Physiology and Pathophysiology of Marathon Running: A narrative Review
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Exercise to Mend Aged-tissue Crosstalk in Bone Targeting Osteoporosis & Osteoarthritis
Little, S. E., Rubin, J. E., Diekman, B. O., Rubin, C. T., McGrath, C., Pagnotti, G. M., Klett, E. L., & Styner, M. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.08.011 · Cited by 30
Metadata
- Authors
- Frodermann, V., Rohde, D., Courties, G., Severe, N., Schloss, M. J., Amatullah, H., McAlpine, C. S., Cremer, S., Hoyer, F. F., Ji, F., van Koeverden, I. D., Herisson, F., Honold, L., Masson, G. S., Zhang, S., Grune, J., Iwamoto, Y., Schmidt, S. P., Wojtkiewicz, G. R., Lee, I.-H., Gustafsson, K., Pasterkamp, G., de Jager, S. C. A., Sadreyev, R. I., MacFadyen, J., Libby, P., Ridker, P., Scadden, D. T., Naxerova, K., Jeffrey, K. L., Swirski, F. K., & Nahrendorf, M.
- Affiliations
- Harvard University (US)
- University Medical Center Utrecht (NL)
- Brigham and Women's Hospital (US)
- Corresponding author
- Nahrendorf, Matthias
- ORCID
- Frodermann, Vanessa
- Rohde, David
- Courties, Gabriel
- Schloss, Maximilian J.
- Amatullah, Hajera
- McAlpine, Cameron S.
- Cremer, Sebastian
- Hoyer, Friedrich F.
- Ji, Fei
- Zhang, Shuang
- Grune, Jana
- Iwamoto, Yoshiko
- Wojtkiewicz, Gregory R.
- Lee, I-Hsiu
- Gustafsson, Karin
- Pasterkamp, Gerard
- de Jager, Saskia C. A.
- Sadreyev, Ruslan I.
- Libby, Peter
- Ridker, Paul
- Scadden, David T.
- Naxerova, Kamila
- Jeffrey, Kate L.
- Nahrendorf, Matthias
- Venue
- Nature Medicine
- Published
- 2019-11
- Volume
- 25
- Issue
- 11
- Pages
- 1761-1771
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6858591
- OpenAlex
- W2982848656
- Cited by
- 292
- References
- 79
- Citations by year
- 2026: 39 · 2025: 51 · 2024: 42 · 2023: 32 · 2022: 51 · 2021: 47 · 2020: 26 · 2019: 3
- FWCI
- 22.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL139598)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- physical activity, voluntary running, hematopoietic stem and progenitor cells, leukocytosis, atherosclerosis, cardiovascular inflammation, leptin, leptin receptor, bone marrow microenvironment, adipose tissue, emergency hematopoiesis, PRRX1, epigenome, transcriptome
- MeSH terms
- Epigenome, Adipose Tissue, Animals, Cardiovascular Diseases, Hematopoiesis, Hematopoietic Stem Cells, Humans, Inflammation, Leukocytes, Leukocytosis, Physical Conditioning, Animal, Exercise, Homeodomain Proteins, Atherosclerosis, Mice, Receptors, Leptin, Sedentary Behavior, Transcriptome
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