A circadian clock in macrophages controls inflammatory immune responses
Open accessAbstract
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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Conversely, there are hints that owing to an overshooting proinflammatory cytokine response, the immediate defense of antigen is impaired during sleep, particularly during SWS.
“Conversely, there are hints that owing to an overshooting proinflammatory cytokine response, the immediate defense of antigen is impaired during sleep, particularly during SWS (508,627,693,779).”
From About Sleep's Role in Memory (2013) · cites this paper as [627]
The Discussion (page not supplied) suggests that excessive macrophage responsiveness may be detrimental and links proinflammatory cytokine secretion to time-of-day differences in endotoxic-shock mortality. It does not say that immediate defense against an antigen is impaired during sleep, particularly slow-wave sleep. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn combination, these data support the view that sleep favors an accumulation of T cells in lymph nodes, and there might be a parallel effect on APC migration.
“In combination, these data support the view that sleep favors an accumulation of T cells in lymph nodes, and there might be a parallel effect on APC migration (307, 627).”
From About Sleep's Role in Memory (2013) · cites this paper as [627]
The Results (page not available) report circadian changes in T-cell proportions and immune-cell trafficking in the spleen, not T-cell accumulation in lymph nodes during sleep. Searches for sleep-related lymph-node accumulation and APC migration found no passage addressing either point. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- 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)
- 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
- 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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