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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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“By reducing the amount of time needed during tissue collection, data are more consistent in studies with large sample sizes by allowing collection of all samples within a smaller temporal window, which is necessary due to the circadian regulation of cytokine expression (Keller et al., 2009; Fonken et al., 2015) Furthe…”
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“These differences in temporal changes between genes may be due to gene-dependent differences in mRNA stability (Hao & Baltimore, 2009) or fluctuations due to circadian rhythms (Keller et al., 2009) contributing to temporal changes in inflammatory gene expression after systemic inflammation.”
BackgroundMeasuring Circadian Clock Function in Human Cells
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“(Keller et al., 2009), hair follicle cells (Akashi et al.”
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“Circadian expression in LPS induces immune pathways at multiple levels ranging from signal reception via signal transduction to response generation and interestingly, gene transcription of AP-1 or TLR4 inhibitory molecules such as CD80 and MD-1, indicating their circadian transcription (Keller et al., 2009).”
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“As spleen composition also varies by time-of-day (Keller et al., 2009), it is also possible that tumors disrupt circadian differences in splenocyte diversity by increased myelopoiesis.”
BackgroundTime is on the Immune System's Side, Yes it is.
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Leung, J. M., & Martinez, M. E. (2020) · Current Environmental Health Reports · doi:10.1007/s40572-020-00285-2 · Cited by 20
Matryba, P., Gawalski, K., Ciesielska, I., Horvath, A., Bartoszewicz, Z., Sieńko, J., Ambroziak, U., Malesa-Tarasiuk, K., Staniszewska, A., Gołąb, J., et al. (2022) · Vaccines · doi:10.3390/vaccines10030443 · Cited by 15
“Although, for many years, it has been widely recognized that significant fluctuations in the function of the innate immune system exists [16], such as time-of-day dependent amount of cytokine release by tissue macrophages upon LPS stimulation [17,18] or neutrophil recruitment [19], recent experiments shed new light on…”
BackgroundFrom immune homeostasis to inflammation, a question of rhythms
Nobis, C. C., Labrecque, N., & Cermakian, N. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.09.001 · Cited by 16
Chen, S., Fuller, K. K., Dunlap, J. C., & Loros, J. J. (2018) · Journal of Biological Rhythms · doi:10.1177/0748730417745178 · Cited by 15
“In immune cells such as macrophages, the molecular clock is cell autonomous (Keller et al., 2009) and drives up to 8% of the transcriptome.”
Yeh, C. H., Li, C., Glick, R. M., Schlenk, E. A., Albers, K. M., Suen, L. K. P., Lukkahatai, N., Salen, N., Pandiri, S., Ma, W., et al. (2020) · Trials · doi:10.1186/s13063-019-4016-x · Cited by 13
Moustafa, A. (2021) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.621188 · Cited by 15
“In rodents, increased proliferation of lymphocytes in lymph nodes and the spleen during the day has been demonstrated (72), while more lymphocytes have been reported to exist in the thymus and spleen at night (6, 73).”
BackgroundCircadiOmic medicine and aging
TABIBZADEH, S. S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101424 · Cited by 17
Sun, Z., Yuan, W., Li, L., Cai, H., Mao, X., Zhang, L., Zang, G., & Wang, Z. (2022) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-022-10225-0 · Cited by 15
“Some studies intended to explore the secretion peak of IL-6, TNF-α, and other cytokines and chemokines and found that the secretion peaked at the end of rest (ZT8-12) [27, 28], so 1 3 we chose the peak time to detect indicators.”
BackgroundThe time dimension to stroke: Circadian effects on stroke outcomes and mechanisms
Kamat, P. K., Khan, M. B., Smith, C. M., Siddiqui, S., Baban, B., Dhandapani, K. M., & Hess, D. C. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105457 · Cited by 16
Katoku-Kikyo, N., Lim, S., Yuan, C., Koroth, J., Nakagawa, Y., Bradley, E. W., & Kikyo, N. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002419 · Cited by 13
Towards improving the prognosis of stroke through targeting the circadian clock system
Khan, S., Siddique, R., Liu, Y., Yong, V. W., & Xue, M. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.88370 · Cited by 18
“…of CRY1/2 increases the basal levels of IL-6, tumor necrosis factor, and CXCL1 in macrophages (44), indicating that clock genes are involved in the regulation of the molecular effectors of pro-inflammatory pathways, which are largely associated with the development and severity of stroke (51,52).”
BackgroundCircadian gating: concepts, processes, and opportunities
Paajanen, P., Kimmey, J. M., & Dodd, A. N. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2023.0346 · Cited by 15
“…fluctuation in the production of proinflammatory cytokines such as interleukin (IL)-6, IL-12(p40), and chemokines including CCL2, CCL5 and CXCL1, with a greater response to LPS at subjective dusk, compared with the response to LPS at subjective dawn, when under free-running conditions [20,21].”
Hirai, T., Tanaka, K., & Togari, A. (2015) · Biology Open · doi:10.1242/bio.012617 · Cited by 15
“Furthermore, previous studies indicated that the circadian clock was intimately associated with pathophysiological responses to environmental stress (Fu and Lee, 2003; Zheng et al., 2007; Keller et al., 2009; Sukumaran et al., 2011).”
BackgroundCancer and cancer survival modulates brain and behavior in a time-of-day-dependent manner in mice
dos Santos, J. C., Bever, S. R., Sullivan, K. A., & Pyter, L. M. (2019) · Scientific Reports · doi:10.1038/s41598-019-42880-w · Cited by 15
Dan, Y., Zhao, C., Mao, Y., Wu, Q., He, Y.-S., Hu, Y., Xiang, K., Yang, X., Sam, N. B., Wu, G., et al. (2021) · Lupus · doi:10.1177/0961203321989794 · Cited by 16
Time-Dependent Effects of Localized Inflammation on Peripheral Clock Gene Expression in Rats
Westfall, S., Aguilar‐Valles, A., Mongrain, V., Luheshi, G. N., & Cermakian, N. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059808 · Cited by 17
Motiei, M., Abu‐Dawud, R., Relógio, A., & Assaf, C. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105451 · Cited by 14
Janev, A., Zupančič, D., Veranič, P., & Kuret, T. (2025) · Journal of Innate Immunity · doi:10.1159/000546901 · Cited by 15
“These findings align with earlier research showing that 5–8% of the macrophage transcriptome is regulated by the circadian clock, including key pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β [124].”
Biological functions of melatonin in relation to pathogenesis of oral lichen planus
Chaiyarit, P., Luengtrakoon, K., Wannakasemsuk, W., Vichitrananda, V., Klanrit, P., Hormdee, D., & Noisombut, R. (2017) · Medical Hypotheses · doi:10.1016/j.mehy.2017.05.021 · Cited by 14
Disrupted-in-schizophrenia 1 enhances the quality of circadian rhythm by stabilizing BMAL1
Lee, S. B., Park, J., Kwak, Y., Park, Y.-U., Nhung, T. T. M., Suh, B. K., Woo, Y., Suh, Y., Cho, E., Cho, S., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01212-1 · Cited by 14
NSAID chronotherapy after impacted third molar extraction: a randomized controlled trial
Tamimi, Z., Abusamak, M., Al‐Waeli, H., Al-Tamimi, M., Habashneh, R. A., Ghanim, M., Al-Nusair, M., Gao, Q., Nicolau, B. F., & Tamimi, F. (2022) · Oral and Maxillofacial Surgery · doi:10.1007/s10006-021-01029-8 · Cited by 14
Porcacchia, A. S., Câmara, D. A. D., Andersen, M. L., & Tufik, S. B. (2021) · European Journal of Cancer Prevention · doi:10.1097/cej.0000000000000685 · Cited by 14
“They control diverse functions: sleep and wake up (Wulff et al., 2009), hormonal synthesis (Oster et al., 2006), body temperature (Cajochen et al., 2005), digestive secretions (Froy, 2010), and immune responses (Keller et al., 2009), among others.”
BackgroundImplications of sleep disorders for periodontitis
Chen, L., Wang, N., Jinmei, Z., & Yang, J. (2022) · Sleep And Breathing · doi:10.1007/s11325-022-02769-x · Cited by 14
“Such circadian disturbance will influence immune cells, bone cells, and fibroblasts in the periodontal tissues impairing defense mechanisms [27–29].”
BackgroundDawn to Dusk: Diurnal Rhythm of the Immune Response in Rainbow Trout (Oncorhynchus Mykiss)
Montero, R., Strzelczyk, J. E., Chan, J. T. H., Verleih, M., Rebl, A., Goldammer, T., Köllner, B., & Korytář, T. (2019) · Biology · doi:10.3390/biology9010008 · Cited by 14
“Recently, circadian rhythms in rodent models were shown to control transcriptional activity of peritoneal macrophages, the inflammatory response of splenic macrophages and also the recruitment of cells to the inflammation site [29,37].”
BackgroundResultYadav, S. K., Haldar, C., & Singh, S. S. (2011) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2011.08.003 · Cited by 14
Crosstalk between circadian clocks and pathogen niche
Borrmann, H., & Rijo‐Ferreira, F. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012157 · Cited by 11
“Around 8% of the transcriptome from murine peritoneal macrophages is under circadian regulation [30], and deletion of Bmal1 in T cells reduced rhythmic cell-intrinsic receptor expression in mice [31].”
BackgroundAl-Shami, A., Crisostomo, J., Wilkins, C., Xu, N., Humphries, J., Chang, W. C., Anderson, S. J., & Oravecz, T. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1203534 · Cited by 13
“by the circadian clock (7) and was also significantly upregulated in human dermal microvascular endothelial cells after activation with thrombin (8).”
BackgroundThe Metronome of Symbiosis: Interactions Between Microbes and the Host Circadian Clock
Heath-Heckman, E. (2016) · Integrative and Comparative Biology · doi:10.1093/icb/icw067 · Cited by 13
“…processivity and the transcription of many genes in gut epithelial and immune cells, is highly circadian (Froy and Chapnik 2007; Hoogerwerf et al. 2008; Keller et al. 2009), there is likely an interface between the circadian rhythmicity of the gut and the physiological effects of symbionts therein.”
BackgroundInfluentialRhythm on a chip: circadian entrainment in vitro is the next frontier in body-on-a chip technology
Fustin, J., Li, M., Gao, X., Chen, Q., Cheng, T., & Stewart, A. G. (2019) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2019.09.005 · Cited by 13
Molecular biology of periodontal ligament fibroblasts and orthodontic tooth movement
Hilbert, D. A., Beisel-Memmert, S., Marciniak, J., & Jäger, A. (2019) · Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie · doi:10.1007/s00056-019-00195-5 · Cited by 13
Nutrients and the Circadian Clock: A Partnership Controlling Adipose Tissue Function and Health
Ribas‐Latre, A., & Eckel‐Mahan, K. L. (2022) · Nutrients · doi:10.3390/nu14102084 · Cited by 14
“Immune cells have autonomous rhythms, as demonstrated by the ex vivo culture of macrophages from the spleen, which can maintain rhythmic production of TNF-alpha and interleukin 6 (IL-6) [42].”
BackgroundHarding, B. N., Aguilar, R., Espinosa, A., Castaño‐Vinyals, G., Papantoniou, K., Navarrete, J. M., Faro, P. S., Torrejón, A., Dobaño, C., Moncunill, G., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.776917 · Cited by 14
“Most immune cells express circadian clock genes (3, 4), which have profound impacts on cellular abundance and rate of DNA synthesis (5, 6).”
BackgroundBonda, T. A., Kamiński, K. A., Kożuch, M., Kozieradzka, A., Wojtkowska, I., Dobrzycki, S., Kralisz, P., Nowak, K. S., Prokopczuk, P., & Musial, W. J. (2010) · Cytokine · doi:10.1016/j.cyto.2010.01.007 · Cited by 13
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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