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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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BackgroundInfluentialCircadian control of pain and neuroinflammation
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“Under homeostatic conditions, macrophages rhythmically express 1,400 genes (23), of which a significant portion have immune function.”
BackgroundInfluenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD
Sundar, I. K., Ahmad, T., Yao, H., Hwang, J., Gerloff, J., Lawrence, B. P., Sellix, M. T., & Rahman, I. (2015) · Scientific Reports · doi:10.1038/srep09927 · Cited by 84
“In the present study, analysis of clock gene expression revealed a significant impact of IAV infection on the expression of core clock genes.”
BackgroundMoon, S., Hong, Y.-S., Ju, J. H., Kwok, S., Park, S., & Min, J.-K. (2013) · The Journal of Rheumatology · doi:10.3899/jrheum.130356 · Cited by 82
Heath-Heckman, E., Peyer, S. M., Whistler, C. A., Apicella, M. A., Goldman, W. E., & McFall‐Ngai, M. (2013) · mBio · doi:10.1128/mbio.00167-13 · Cited by 86
“For example, in the epithelium-immune-microbiota axis of the gut, the transcriptomes of both immune and epithelial components of the gut (1, 8, 9) are on a profound circadian rhythm controlled by the clock genes (e.”
BackgroundHopwood, T. W., Hall, S., Begley, N., Forman, R. A., Brown, S. L., Vonslow, R. M., Saer, B., Little, M. C., Murphy, E. A., Hurst, R., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-22021-5 · Cited by 86
Crosstalk between circadian rhythmicity, mitochondrial dynamics and macrophage bactericidal activity
Oliva, J., Moreno‐Altamirano, M. M. B., Pineda, B., Cauich-Sánchez, P. I., & Sánchez‐García, F. J. (2014) · Immunology · doi:10.1111/imm.12329 · Cited by 81
Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway
Duez, H., & Pourcet, B. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.630536 · Cited by 85
Mechanism for 12 Hr Rhythm Generation by the Circadian Clock
Westermark, P. O., & Herzel, H. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.03.013 · Cited by 77
“Up to 10% of all mammalian genes, depending on tissue, measurement, and analysis method, are regulated by the circadian clock and thus oscillate in their expression with a period of around 24 hr (Panda et al., 2002; Storch et al., 2002; Ueda et al., 2002; Hughes et al., 2009; Keller et al., 2009).”
BackgroundTemporal Regulation of Cytokines by the Circadian Clock
Nakao, A. (2014) · Journal of Immunology Research · doi:10.1155/2014/614529 · Cited by 85
A circadian based inflammatory response – implications for respiratory disease and treatment
Comas, M., Gordon, C. J., Oliver, B. G. G., Stow, N. W., King, G. G., Sharma, P. K., Ammit, A. J., Grunstein, R. R., & Phillips, C. L. (2017) · Sleep Science and Practice · doi:10.1186/s41606-017-0019-2 · Cited by 79
Circadian rhythms and renal pathophysiology
Mohandas, R., Douma, L. G., Scindia, Y. M., & Gumz, M. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148277 · Cited by 82
The circadian system, sleep, and the health/disease balance: a conceptual review
Roenneberg, T., Foster, F., & Klerman, E. B. (2022) · Journal of Sleep Research · doi:10.1111/jsr.13621 · Cited by 81
“Similarly, the moderation of the circadian clock on immune responses is well established (Keller et al., 2009), but growing evidence indicates that the circadian system is also under the influence of the immune system (Coogan &”
BackgroundThe Circadian Clock Controls Sunburn Apoptosis and Erythema in Mouse Skin
Gaddameedhi, S., Selby, C. P., Kemp, M. G., Ye, R., & Sancar, A. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.508 · Cited by 81
“In addition, it was recently reported that TNF-α levels are influenced by the circadian rhythm in mouse macrophages (Keller et al., 2009).”
BackgroundIntra- and inter-day variation of cytokines and chemokines in tears of healthy subjects
Benito, M. J., González-García, M. J., Tesón, M., García, N., Fernández, I., Calonge, M., & Enríquez‐de‐Salamanca, A. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2013.12.017 · Cited by 81
Zhao, Y., Liu, M., Chan, X. Y., Tan, S. Y., Subramaniam, S., Fan, Y., Loh, E., Chang, K. T. E., Tan, T. C., & Chen, Q. (2017) · Blood · doi:10.1182/blood-2017-04-778779 · Cited by 83
Circadian systems biology: When time matters
Fuhr, L., Abreu, M., Pett, J. P., & Relógio, A. (2015) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2015.07.001 · Cited by 84
“Indeed independent studies point to circadian influence on the immune system [32], themetabolism of different metabolites [33], bone formation [34], sleep–awake cycles [35], memory consolidation [36], blood pressure, body temperature, cell division and proliferation [37], hormone regulation [38], apoptosis”
BackgroundGastric Bypass and Sleeve Gastrectomy: the Same Impact on IL-6 and TNF-α. Prospective Clinical Trial
Viana, E. C., Araujo-Dasilio, K. L., Miguel, G. P. S., Bressan, J., Lemos, E. M., Moysés, M. R., Abreu, G. R., Azevedo, J. L. M. C., de Carvalho, P. S., Passos‐Bueno, M. R. S., et al. (2013) · Obesity Surgery · doi:10.1007/s11695-013-0894-2 · Cited by 78
“It is important to note that previous work has demonstrated crosstalk between IL-6 and TNF-α expression [43, 44], and the expression of these cytokines was affected by the NF-κB regulatory network [45].”
BackgroundBiglari, B., Swing, T., Child, C., Büchler, A., Westhauser, F., Brückner, T., Ferbert, T., Gerner, H. J., & Moghaddam, A. (2015) · Spinal Cord · doi:10.1038/sc.2015.28 · Cited by 78
The chemistry of negotiation: Rhythmic, glycan-driven acidification in a symbiotic conversation
Schwartzman, J. A., Koch, E. J., Heath-Heckman, E., Zhou, L. H., Kremer, N., McFall‐Ngai, M., & Ruby, E. G. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1418580112 · Cited by 76
“Appl Environ Microbiol 74(13):4059–4069.”
BackgroundMethodInfluentialCircadian clock: a regulator of the immunity in cancer
Zhang, Z., Zeng, P., Gao, W., Zhou, Q., Feng, T., & Tian, X. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00721-2 · Cited by 80
Rosselot, A. E., Hong, C. I., & Moore, S. R. (2015) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000227 · Cited by 76
“Macrophages maintain robust circadian rhythms, which results in rhythmic expression of proinflammatory cytokines [21].”
BackgroundXi, Y., Yan, J., Li, M., Ying, S., & Shi, Z. (2019) · Poultry Science · doi:10.3382/ps/pez357 · Cited by 76
Circadian Control of Inflammatory Processes in Atherosclerosis and Its Complications
Steffens, S., Winter, C., Schloss, M. J., Hidalgo, A., Weber, C., & Soehnlein, O. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309374 · Cited by 78
Fonken, L. K., Kitt, M. M., Gaudet, A. D., Barrientos, R. M., Watkins, L. R., & Maier, S. F. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.07.019 · Cited by 77
“Diurnal variations in immune responses are regulated in part by circadian rhythms in inflammatory cells (Arjona and Sarkar, 2006; Boivin et al., 2003; Bollinger et al., 2011; Fonken et al., 2015; Hayashi et al., 2007; Keller et al., 2009; Silver et al., 2012).”
BackgroundResultInfluentialReece, S. E., Prior, K. F., & Mideo, N. (2017) · Journal of Biological Rhythms · doi:10.1177/0748730417718904 · Cited by 78
“Since immune responses are involved in wound healing and are known to be circadian (Curtis et al., 2015; Davies et al., 2013; Keller et al., 2009; Petrovsky et al., 2003; Stevenson et al., 1992), it is likely that time-of-day matters to the host.”
BackgroundCircadian Clock Regulates Inflammation and the Development of Neurodegeneration
Wang, X., & Li, L. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.696554 · Cited by 78
“It has been reported that approximately 8% of genes are under circadian control in macrophages and more complex molecular mechanisms may be underlying the circadian clock regulation of the innate immune response (Keller et al., 2009).”
BackgroundWillison, L. D., Kudo, T., Loh, D. H., Kuljis, D. A., & Colwell, C. S. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.01.014 · Cited by 73
“Themolecular clock is found in many of the key cells involved in the immune response and disruption of the circadian system alters the immune response (e.g. Castanon-Cervantes et al., 2010; Froy and Chapnik, 2007; Keller et al., 2009).”
Environmental Circadian Disruption Elevates the IL-6 Response to Lipopolysaccharide in Blood
Adams, K. L., Castañón‐Cervantes, O., Evans, J. A., & Davidson, A. J. (2013) · Journal of Biological Rhythms · doi:10.1177/0748730413494561 · Cited by 71
“Isolated macrophages exhibit rhythms in clock gene expression, phagocytic activity, and response to the bacterial endotoxin lipopolysaccharide (LPS) (Gibbs et al., 2012; Keller et al., 2009).”
BackgroundThe estrogen–macrophage interplay in the homeostasis of the female reproductive tract
Pepe, G., Locati, M., Torre, S. D., Mornata, F., Cignarella, A., Maggi, A. C., & Vegeto, E. (2018) · Human Reproduction Update · doi:10.1093/humupd/dmy026 · Cited by 78
“Macrophages express circadian clock genes also independently from the brain 23 pacemaker (Boivin et al., 2003; Keller et al., 2009); interestingly, macrophage inflammatory responses 24 follow circadian rhythmicity and require clock genes to efficiently take place (Spengler et al., 2012; Oliva-25…”
BackgroundCircadian rhythms in adaptive immunity and vaccination
Cermakian, N., Stegeman, S. K., Tekade, K., & Labrecque, N. (2021) · Seminars in Immunopathology · doi:10.1007/s00281-021-00903-7 · Cited by 70
“, Per2, Reverbα) show rhythmic expression in mouse lymph nodes (LNs), lymphoid organs which are the site of the induction of the T and B cell response, and are composed in large proportions of these cell types [3, 4].”
BackgroundCircadian molecular clock disruption in chronic pulmonary diseases
Giri, A., Wang, Q., Rahman, I., & Sundar, I. K. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.04.002 · Cited by 70
Immunometabolism around the Clock
Carroll, R. G., Timmons, G. A., Cervantes‐Silva, M. P., Kennedy, O. D., & Curtis, A. M. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.04.013 · Cited by 72
Cardinali, D. P., Brown, G. M., & Pandi-Perumal, S. R. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819975-6.00023-6 · Cited by 76
Liu, B., Page, A. J., Hatzinikolas, G., Chen, M., Wittert, G., & Heilbronn, L. K. (2018) · Endocrinology · doi:10.1210/en.2018-00701 · Cited by 69
Aguilar‐López, B. A., Moreno‐Altamirano, M. M. B., Dockrell, H. M., Duchen, M. R., & Sánchez‐García, F. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00051 · Cited by 73
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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