Cited by 843Circadian rhythm and melatoninSleep and Work-Related FatigueImmune Response and Inflammation

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A circadian clock in macrophages controls inflammatory immune responses

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Keller, Maren, Mazuch, Jeannine, Abraham, Ute, Eom, Gina D., Herzog, Erik D., Volk, Hans-Dieter, Kramer, Achim, Maier, Bert·2009·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0906361106PMC PMC2795539

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Abstract

Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo. These clocks regulate circadian rhythms in inflammatory innate immune functions: Isolated spleen cells stimulated with bacterial endotoxin at different circadian times display circadian rhythms in TNF-α and IL-6 secretion. Interestingly, we found that these rhythms are not driven by systemic glucocorticoid variations nor are they due to the detected circadian fluctuation in the cellular constitution of the spleen. Rather, a local circadian clock operative in splenic macrophages likely governs these oscillations as indicated by endotoxin stimulation experiments in rhythmic primary cell cultures. On the molecular level, we show that >8% of the macrophage transcriptome oscillates in a circadian fashion, including many important regulators for pathogen recognition and cytokine secretion. As such, understanding the cross-talk between the circadian clock and the immune system provides insights into the timing mechanism of physiological and pathophysiological immune functions.

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Yamazaki, S., Numano, R., Abe, M., Hida, A., Takahashi, R.-I., Ueda, M., Block, G. D., Sakaki, Y., Menaker, M., & Tei, H. (2000) · Science · doi:10.1126/science.288.5466.682 · Cited by 1,907
Resetting of circadian time in peripheral tissues by glucocorticoid signaling
Balsalobre, A., Brown, S. A., Marcacci, L., Tronche, F., Kellendonk, C., Reichardt, H. M., Schütz, G., & Schibler, U. (2000) · Science · doi:10.1126/science.289.5488.2344 · Cited by 1,859
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Barnes, P. J., Adcock, I. M., Spedding, M., & Vanhoutte, P. M. (1993) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(93)90184-l · Cited by 725
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Background
Pre- and Postshift Levels of Inflammatory Biomarkers and Dna Damage in Non-Bitumen-Exposed Construction Workers—Subpopulation of the German Human Bitumen Study
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“Oscillations during the course of a day were also reported for the cellular composition of the immune response (Born et al. 1997; Keller et al. 2009).”
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“9% NaCl, except for inconsiderable, in view of the research objective, varia tion of mRNATNFα, since the latter is connected with nonspecific circadian fluctuations of gene TNFα expression in mononuclear suspension in vitro [19, 20].”
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Repeated Changes to the Gravitational Field Negatively Affect the Serum Concentration of Select Growth Factors and Cytokines
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“Third, inflammatory processes, which have been shown to affect amygdala function (Inagaki et al., 2012; Muscatell et al., 2015, 2016), also follow circadian patterns of variation (Keller et al., 2009; Narasimamurthy et al., 2012; Gibbs et al., 2014).”
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Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol
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O’Donnell, A. J., Mideo, N., & Reece, S. E. (2014) · Malaria Journal · doi:10.1186/1475-2875-13-503 · Cited by 7
“Many components of mammalian blood, including RBC [2,8], and immune factors in the blood and spleen exhibit circadian periodicity and often appear to be upregulated in the dark phase of the day [9-17].”
A damage accumulation model identifies distinct aging regimes across species
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“One hypothesis is that noise is due to circadian fluctuations in immune functions that remove damaged and/or senescent cells 47–51 (Supplementary Note 4).”
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Differential weight loss with intermittent fasting or daily calorie restriction in low‐ and high‐fitness phenotypes
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“Cytokine levels are under circadian control, and perhaps the timing of serum collection influenced cytokine levels somewhat (Keller et al., 2009; Liu et al., 2018).”
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Seeing the forest and trees: whole‐body and whole‐brain imaging for circadian biology
Ode, K. L., & Ueda, H. R. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12511 · Cited by 6
“showed that circadian clock acting in macrophage fulfils the circadian cytokine response [55], and Gibbs et al.”
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Characterization of Novel Fragment Antibodies Against TNF-alpha Isolated Using Phage Display Technique.
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“In addition to the whole-body immune system, the circadian rhythm exists in several immune cells, such as monocytes [48], macrophages [49], T cells [50], B cells and dendritic cells [51].”
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“Approximately 8% of the macrophage transcriptome, which is closely linked to physiological processes such as glucose metabolism, lipid metabolism, and vascular integrity, is under the regulation of the molecular clock [9].”
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“Mechanistic studies show that TLR4-expressing splenocytes (predominatly monocytes/macrophages) exhibit circadian-regulated cytokine secretion of TNF-α and IL-6 following LPS stimulation, indicating circadian modulation of TLR4 downstream signaling [61].”
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“Further, local levels of these cytokines within the spleen were comparable between both sets of mice at 4h PI suggesting that the diurnal phenotype of MMMs is likely due to cell-autonomous circadian pathways, and not mediated by localised or systemic differences in cytokine levels (38, 48).”
Background
Reciprocal Regulation of Circadian Rhythms and Immune Function
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The Use of Mouse Splenocytes to Assess Pathogen-associated Molecular Pattern Influence on Clock Gene Expression
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Deficiency of circadian gene cryptochromes in bone marrow‐derived cells protects against atherosclerosis in LDLR −/− mice
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Systems Biology and Innate Immunity
Kobayashi, S. D., & DeLeo, F. R. (2013) · Journal of Innate Immunity · doi:10.1159/000347135 · Cited by 5
“For example, a circadian clock in macrophages regulates chang-es in expression of genes important for pathogen recognition and the innate immune response [18] , and phagocytosis is circadian-regulated in Drosophila [19] .”
Background
The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophagesPreprint
Barr, H. J., Caldwell, S. K., Reimertz, J. M., Depp, C., Walker, A. J., Marsh, S. E., Gupte, A. S., Hingerl, M., Patel, J., Park, S.-O., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.08.693074 · Cited by 8

Authors: Keller, M., Mazuch, J., Abraham, U., Eom, G. D., Herzog, E. D., Volk, H.-D., Kramer, A., & Maier, B.
Affiliations: Laboratory of Chronobiology, Institute for Medical Immunology, and Research Center ImmunoSciences and
Washington University in St. Louis (US)
Charité – Universitätsmedizin Berlin (DE)
ORCID: Abraham, Ute
Herzog, Erik D.
Volk, Hans-Dieter
Kramer, Achim
Maier, Bert
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2009-12-15
Volume: 106
Issue: 50
Pages: 21407-21412
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0906361106
PMC: PMC2795539
OpenAlex: W2090209293
Cited by: 843
References: 44
Citations by year: 2026: 58 · 2025: 64 · 2024: 44 · 2023: 55 · 2022: 57 · 2021: 80 · 2020: 71 · 2019: 59 · 2018: 48 · 2017: 56 · 2016: 51 · 2015: 53 · 2014: 47 · 2013: 42 · 2012: 22
FWCI: 8.38
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: European Commission
Deutsche Forschungsgemeinschaft
National Institutes of Health
National Institute of Mental Health (R01MH063104, MH 63104)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: circadian clock, macrophages, innate immunity, inflammatory immune response, circadian rhythm, endotoxin stimulation, TNF-α, interleukin-6, cytokine production, splenic macrophages, glucocorticoids, pathogen recognition
MeSH terms: Animals, Circadian Rhythm, Gene Expression Regulation, Immunity, Innate, Inflammation, Lipopolysaccharides, Lymph Nodes, Macrophages, RNA, Messenger, Spleen, Tumor Necrosis Factor-alpha, Interleukin-6, Macrophages, Peritoneal, Mice

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A circadian clock in macrophages controls inflammatory immune responses

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