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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Physical activity inhibits inflammatory responses.
“Instead, PA reinforces cardiorespiratory fitness, 31 inhibits inflammatory responses, 32 and improves glucose metabolism.33”
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“Recently it has been reported that running exercise diminishes leptin production in adipose tissue to regulate HSPCs proliferation and leukocyte production in mice.(195) The impact of exercise on leukocyte production and on HSPC epigenome and transcriptome persists for several weeks.”
BackgroundReactive Oxygen Species Bridge the Gap between Chronic Inflammation and Tumor Development
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“On a cellular level, exercise inhibits leptin production which is normally the main driver for inflammation via proliferation of hematopoietic stem and progenitor cells [102].”
BackgroundExercise and the immune system: taking steps to improve responses to cancer immunotherapy
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“The effect of voluntary exercise on myeloid cells persisted for weeks after exercise cessation and arose from epigenetic alterations in HSPCs 48 .”
BackgroundNaturalizing mouse models for immunology
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Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease
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Modifiable Cardiovascular Risk, Hematopoiesis, and Innate Immunity
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A stem cell aging framework, from mechanisms to interventions
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Self-citationThe Hematopoietic Bone Marrow Niche Ecosystem
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Gut Microbiota and Atherosclerosis—Focusing on the Plaque Stability
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Exercise of high intensity ameliorates hepatic inflammation and the progression of NASH
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“As leptin is positively correlated with BW and adiposity [14], it is possible that some of the beneficial effects of HIIT are induced through leptin-mediated reductions in hematopoiesis.”
BackgroundInfluentialImpact of cholesterol on proinflammatory monocyte production by the bone marrow
Stiekema, L. C. A., Willemsen, L., Kaiser, Y., Prange, K. H. M., Wareham, N. J., Boekholdt, S. M., Kuijk, C., de Winther, M. P. J., Voermans, C., Nahrendorf, M., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab465 · Cited by 87 · see citing works
T Cell Immunosenescence in Aging, Obesity, and Cardiovascular Disease
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“In addition, environmental stresses such as lack of exercise and sleep disturbance have been shown to accelerate the progression of atherosclerosis by increasing the production of inflammatory monocytes and neutrophils in the bone marrow [7,8].”
BackgroundYang, X., Zhao, S., Wang, S., Cao, X., Xu, Y., Yan, M., Pang, M., Yi, F., & Wang, H. (2023) · BMC Medicine · doi:10.1186/s12916-023-02770-5 · Cited by 85 · see citing works
Methyl-CpG-binding 2 K271 lactylation-mediated M2 macrophage polarization inhibits atherosclerosis
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“Global DNA methylation in blood has been shown to be upregulated after exercise [8, 9].”
Age-related bone diseases: Role of inflammaging
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Exercise and immunometabolic regulation in cancer
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Neural Mechanisms in Cardiovascular Health and Disease
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Exercise and adrenergic regulation of immunity
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Environmental influences on clonal hematopoiesis
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“In contrast, a recent study suggests that exercise reduces leptin, a hormone that governs energy expenditure, and reduction of leptin instructs BMSCs to express HSC niche factors to promote HSC quiescence (Frodermann et al., 2019).”
BackgroundThe Emerging Role of Irisin in Cardiovascular Diseases
Fu, J., Li, F., Tang, Y., Cai, L., Zeng, C., Yang, Y., & Yang, J. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.121.022453 · Cited by 72 · see citing works
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Immune remodeling and atrial fibrillation
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“It has been suggested that regular voluntary physical activity alters the proliferation of hematopoietic stem and progenitor cells via modulation of their niche and reduces the inflammatory leukocyte output (Frodermann et al., 2019).”
BackgroundSystematic profiling reveals betaine as an exercise mimetic for geroprotection
Geng, L., Ping, J., Wu, R., Yan, H., Zhang, H., Zhuang, Y., Ning, T., Wang, J., Liang, C., Zhang, J., et al. (2025) · Cell · doi:10.1016/j.cell.2025.06.001 · Cited by 73 · see citing works
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“Recent animal studies have shown that exercise and healthy sleep attenuate leucopoietic activity and atherosclerosis, suggesting these approaches may impart benefits via the leucopoietic-arterial axis.(18,19) Future studies could examine the impact of these therapies on CVD outcomes in pollution-exposed individuals.”
BackgroundExploring cardiac macrophage heterogeneity in the healthy and diseased myocardium
Zaman, R., Hamidzada, H., & Epelman, S. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.09.005 · Cited by 65 · see citing works
Exercise tolls the bell for key mediators of low-grade inflammation in dysmetabolic conditions
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“153 With age, MuSCs exhibit a decrease in cyclin D1 expression and a corresponding slowing of activation out of quiescence.”
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Obesity and Cardiovascular Disease: The Emerging Role of Inflammation
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“CHIP: In the Women’s Health Initiative study, CHIP increased with increased BMI in post-menopausal women (highest in those with BMI>30 vs. BMI 27–30 kg/m2 compared to normal weight women) (65).”
BackgroundInfluentialInnate Immunity System in Patients With Cardiovascular and Kidney Disease
Zoccali, C., & Mallamaci, F. (2023) · Circulation Research · doi:10.1161/circresaha.122.321749 · Cited by 60 · see citing works
Treatment of Obesity in Mitigating Metabolic Risk
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Adipokines and Adipose Tissue-Related Metabolites, Nuts and Cardiovascular Disease
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The Impact of Exercise on Immunity, Metabolism, and Atherosclerosis
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“Even though it has been s own that exercise re uces the proliferation of macrophages in adipose tissue [99], there is no evidence demonstrating that exercise ffects macrophage proliferation in plaques.”
BackgroundInfluentialAnti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba
Ye, W., Wang, J., Little, P. J., Zou, J., Zheng, Z., Lü, J., Yin, Y., Liu, H., Zhang, D., Liu, P., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.09.014 · Cited by 55 · see citing works
Bone-derived factors mediate crosstalk between skeletal and extra-skeletal organs
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Exercise, Physical Activity, and Cardiometabolic Health
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Impact of Acute and Chronic Psychosocial Stress on Vascular Inflammation
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“Regular exercise reduces cardiovascular risk through metabolic and antihypertensive effects (86), and a recent study in mice demonstrated that physical activity (simulated by voluntary wheel running) also mitigates cardiovascular inflammation (42).”
BackgroundAtherosclerosis is a major human killer and non-resolving inflammation is a prime suspect
Fredman, G., & MacNamara, K. C. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab309 · Cited by 52 · see citing works
“chronic leucocytosis which ultimately resulted in reduced atherosclerosis in mice.(100) Whether SPMs or resolution mechanisms are involved in”
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Connection and communication between the nervous and immune systems
Leunig, A., Gianeselli, M., Russo, S. J., & Świrski, F. K. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01199-6 · Cited by 55 · see citing works
“3), where they act as key niche regulators that promote immune cell distribution via circadian signalling 99 or emergency haematopoiesis 100 , and by preventing premature and myeloid-skewed differentiation 101–103 .”
Common Sources of Inflammation and Their Impact on Hematopoietic Stem Cell Biology
Hormaechea-Agulla, D., Le, D., & King, K. (2020) · Current Stem Cell Reports · doi:10.1007/s40778-020-00177-z · Cited by 42 · see citing works
Molecular regulation of hematopoietic stem cell quiescence
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Inflammation Regulates Haematopoietic Stem Cells and Their Niche
Ho, N. P. Y., & Takizawa, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031125 · Cited by 48 · see citing works
“Exercise can also enhance immunity by improving emergency haematopoiesis during LPS infection and sepsis [87].”
BackgroundInfluentialMargraf, A., & Perretti, M. (2022) · Cells · doi:10.3390/cells11111824 · Cited by 45 · see citing works
“Such physical activity furthermore impacts emergency myelopoiesis, and absence or limitations of physical activity must therefore be considered in specific patient subsets, such as intensive care patients [43].”
BackgroundAlterations in endothelial nitric oxide synthase activity and their relevance to blood pressure
Suvorava, T., Metry, S., Pick, S., & Kojda, G. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115256 · Cited by 48 · see citing works
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“In these settings, HSCs LT exhibit an increased myeloid potential and a progressive exhaustion of their self-renewal capacity 22–24 , 56 .”
BackgroundExercise and Adipose Tissue Immunity: Outrunning Inflammation
Winn, N. C., Cottam, M. A., Wasserman, D. H., & Hasty, A. H. (2021) · Obesity · doi:10.1002/oby.23147 · Cited by 43 · see citing works
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“Regular physical exercise can effectively improve metabolism, delay the development of AS, and thus reduce CVD mortality [8-10].”
Dopamine signaling regulates hematopoietic stem and progenitor cell function
Liu, Y., Chen, Q., Jeong, H., Han, D., Fabian, J., Drexler, H. C. A., Stehling, M., Schöler, H. R., & Adams, R. H. (2021) · Blood · doi:10.1182/blood.2020010419 · Cited by 42 · see citing works
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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 41 · see citing works
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The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis
Campbell, R., Docherty, M.-H., Ferenbach, D. A., & Mylonas, K. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.700790 · Cited by 40 · see citing works
Effects of lifestyle factors on leukocytes in cardiovascular health and disease
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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 39 · see citing works
“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
Okamoto, K. (2024) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-024-01539-x · Cited by 37 · see citing works
“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
Hastings, M. H., Castro, C., Freeman, R., Kadir, A. A., Lerchenmüller, C., Li, H., Rhee, J., Roh, J. D., Roh, K., Singh, A. P., et al. (2023) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2023.07.011 · Cited by 34 · see citing works
The cGAS-STING Pathway in Hematopoiesis and Its Physiopathological Significance
Liao, W., Du, C., & Wang, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.573915 · Cited by 34 · see citing works
The gut microbiome in subclinical atherosclerosis: a population-based multiphenotype analysis
Zhu, S., Xu, K., Jiang, Y., Zhu, C., Suo, C., Cui, M., Wang, Y., Yuan, Z., Xue, J., Wang, J., et al. (2021) · Rheumatology · doi:10.1093/rheumatology/keab309 · Cited by 38 · see citing works
Effects of Exercise or Mechanical Stimulation on Bone Development and Bone Repair
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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
Carnevale, D., & Lembo, G. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa151 · Cited by 34 · see citing works
Matrix biophysical cues direct mesenchymal stromal cell functions in immunity
Wong, S. W., Lenzini, S. B., Giovanni, R., Clark-Knowles, K. V., & Shin, J. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.07.075 · Cited by 33 · see citing works
Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity
Zuani, M. D., & Frič, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.827250 · Cited by 34 · see citing works
“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 31 · see citing works
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
Mitroulis, I., Hajishengallis, G., & Chavakis, T. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314215 · Cited by 30 · see citing works
Sun, S., Lai, C., Huang, C., Ren, X., Zhang, T., Zou, J., Tong, Y., Zhou, Q., Lu, J., Shen, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67443-8 · Cited by 34 · see citing works
Physiology and Pathophysiology of Marathon Running: A narrative Review
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- 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 › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Epidemiology › 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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