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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 (508,627,693,779).”
From About Sleep's Role in Memory (2013) · cites this paper as [627]
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“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]
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The Circadian Deadenylase Nocturnin Is Necessary for Stabilization of the iNOS mRNA in Mice
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Systemic Inflammation Disrupts Circadian Rhythms and Diurnal Neuroimmune Dynamics
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“Immune functions demonstrate diurnal oscillations, which is vital for regulating inflammatory responses and immunity maintenance [22–24].”
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The clock‐controlled chemokine contributes to neuroinflammation‐induced depression
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Circadian regulation of innate immunity in animals and humans and implications for human disease
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“established that spleen and lymph nodederived macrophages contain autonomous cellular oscillators with 8% of their transcriptome being expressed in a circadian pattern [46].”
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Achilles is a circadian clock-controlled gene that regulates immune function in Drosophila
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“Well documented circadian rhythms in mammals include: direct trafficking of various immune cells among the blood and organs [4], generating daily variation in gene transcription [5], controlling rhythms in the rate of protein translation [6], and altering functional responses to infection/vaccination [7,8].”
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Mathematical Modeling in Chronobiology
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Time-of-Day Dictates Transcriptional Inflammatory Responses to Cytotoxic Chemotherapy
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“In vitro, the different cell types that compose the brain, including neurons [70], glial [71], epithelial [72], and immune cells [73], have been shown to express rhythms of clock genes.”
BackgroundDiel patterning in the bacterial community associated with the sea anemone Nematostella vectensis
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“In humans (Huang, Ramsey, Marcheva, & Bass, 2011) and mice (Leone et al., 2015), the gut microbiota is time‐of‐day–dependent and is hypothesized to modulate the regulation of host metabolism and immunity (Keller et al., 2009; Liang, Bushman, & FitzGerald, 2015; Thaiss et al., 2014).”
Background
Metadata
- 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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