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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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Sleep disorders, nocturnal blood pressure, and cardiovascular risk: A translational perspective
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Circadian Coordination of Antimicrobial Responses
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Circadian disruption alters mouse lung clock gene expression and lung mechanics
Hadden, H., Soldin, S. J., & Massaro, D. J. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00244.2012 · Cited by 64
The RelB subunit of NFκB acts as a negative regulator of circadian gene expression
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“Accumulating evidence shows the presence of bidirectional links between circadian regulation and inflammatory response.(14-21) Previous studies have demonstrated that stimulation of fibroblasts with tumor necrosis factor-α (TNFα) represses circadian transcription.”
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The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma
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“The molecular clock exists in immune cells (36), including macrophages, where its key functions involve control of inflammatory responses (14, 24).”
BackgroundMicroRNA-21 Controls Circadian Regulation of Apoptosis in Atherosclerotic Lesions
Schober, A., Blay, R. M., Maleki, S. S., Zahedi, F., Winklmaier, A. E., Kakar, M. Y., Baatsch, I. M., Zhu, M., Geißler, C., Fusco, A. E., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.051614 · Cited by 65
Lechasseur, A., Jubinville, É., Routhier, J., Bérubé, J., Hamel-Auger, M., Talbot, M., Lamothe, J., Aubin, S., Paré, M., Beaulieu, M., et al. (2017) · Physiological Reports · doi:10.14814/phy2.13440 · Cited by 63
“…(Panda et al. 2002; So et al. 2009; Bass and Takahashi 2010), immune and inflammatory responses (Oishi et al. 2006; Gibbs et al. 2009, 2014; Keller et al. 2009; Castanon-Cervantes et al. 2010; Ackermann et al. 2012; Scheiermann et al. 2012; Bellet et al. 2013; Sato et al. 2014), lipolysis…”
BackgroundCircadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis
Lee, J. H., & Sancar, A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106284108 · Cited by 65
“Moreover, as TNFα is known to be involved in the inflammatory response, Cry mice which overexpress TNFα are uniquely sensitive to inflammatory stimuli and exhibit a rheumatoid arthritis-like syndrome caused by such stimuli (Keller et al., 2009).”
BackgroundGuerrero‐Vargas, N. N., Salgado‐Delgado, R., Basualdo, M. D. C., García, J., Guzmán‐Ruiz, M. A., Carrero, J. C., Escobar, C., & Buijs, R. M. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.05.012 · Cited by 62
“It has been demonstrated that clock genes are expressed in immune cells such as macrophages (Hayashi et al., 2007; Keller et al., 2009; Silver et al., 2012), lymphocytes (Du et al.”
InfluentialCircadian Clock–Coupled Lung Cellular and Molecular Functions in Chronic Airway Diseases
Sundar, I. K., Yao, H., Sellix, M. T., & Rahman, I. (2015) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2014-0476tr · Cited by 61
Tong, X., Buelow, K. L., Guha, A., Rausch, R., & Yin, L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.340786 · Cited by 66
“The functional circadian clock systems are detected in major immune cells, including macrophages (63), B cells (64, 65), and natural killer cells (66–68).”
BackgroundSuprachiasmatic Astrocytes Modulate the Circadian Clock in Response to TNF-α
Duhart, J. M., Leone, M. J., Paladino, N., Evans, J. A., Castañón‐Cervantes, O., Davidson, A. J., & Golombek, D. A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300450 · Cited by 61
“Indeed, members of both NF-kB and p38 pathways (which are activated by TNF-a) present circadian rhythmicity on murine macrophages (39), and”
BackgroundLogan, R. W., Wynne, O., Levitt, D., Price, D., & Sarkar, D. K. (2013) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2012.0092 · Cited by 59
The circadian clock functions as a potent regulator of allergic reaction
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“2 The specific roles in allergic diseases of the molecular clocks present in immune cells, such as T cells (49, 50), eosinophils (42, 43), basophils (12), macrophages (51), or type-2 innate immune cells, or in organs, such as the lung (52) and skin (53), remain to be investigated.”
BackgroundPalmieri, O., Mazzoccoli, G., Bossa, F., Maglietta, R., Palumbo, O., Ancona, N., Corritore, G., Latiano, T., Martino, G., Rubino, R., et al. (2015) · Chronobiology International · doi:10.3109/07420528.2015.1050726 · Cited by 60
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BackgroundLazado, C. C., Skov, P. V., & Pedersen, P. B. (2016) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2016.06.040 · Cited by 58
Chemical chronobiology: Toward drugs manipulating time
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Self-citationCircadian Clocks in the Hematologic System
Pritchett, D., & Reddy, A. B. (2015) · Journal of Biological Rhythms · doi:10.1177/0748730415592729 · Cited by 59
“• • Cytokine and chemokine expression and LPS-induced cytokine secretion (Hayashi et al., 2007; Keller et al., 2009; Gibbs et al., 2012; Silver et al., 2012a)”
BackgroundRegulation of the clock gene expression in human adipose tissue by weight loss
Pivovarova‐Ramich, O., Gögebakan, Ö., Sucher, S., Groth, J., Murahovschi, V., Kessler, K., Osterhoff, M., Rudovich, N. N., Kramer, A., & Pfeiffer, A. F. H. (2016) · International Journal of Obesity · doi:10.1038/ijo.2016.34 · Cited by 59
Self-citationDigital clocks: simple Boolean models can quantitatively describe circadian systems
Akman, O. E., Watterson, S., Parton, A., Binns, N., Millar, A. J., & Ghazal, P. (2012) · Journal of The Royal Society Interface · doi:10.1098/rsif.2012.0080 · Cited by 65
Light pollution increases West Nile virus competence of a ubiquitous passerine reservoir species
Kernbach, M. E., Newhouse, D., Miller, J. M., Hall, R. J., Gibbons, J., Oberstaller, J., Selechnik, D., Jiang, R. H. Y., Unnasch, T. R., Balakrishnan, C. N., et al. (2019) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2019.1051 · Cited by 59
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The Cutaneous Wound Innate Immunological Microenvironment
Kirchner, S. J., Lei, V., & MacLeod, A. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228748 · Cited by 61
“Even more specifically, cytokine secretion [98] is circadian gated in other non-skin tissues, and so understanding if this is true in wounds would greatly shape our understanding of the immune microenvironment of this disrupted tissue.”
BackgroundDigital clocks: simple Boolean models can quantitatively describe circadian systems
Akman, O. E., Watterson, S., Parton, A., Binns, N., Millar, A. J., & Ghazal, P. (2025) · Figshare · Cited by 57
Circadian clock genes as promising therapeutic targets for autoimmune diseases
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Circadian rhythm disruption in critically ill patients
Felten, M., Dame, C., Lachmann, G., Spies, C., Rubarth, K., Balzer, F., Kramer, A., & Witzenrath, M. (2023) · Acta Physiologica · doi:10.1111/apha.13962 · Cited by 65
Self-citationImmunometabolism: Is it under the eye of the clock?
Early, J. O., & Curtis, A. M. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.10.006 · Cited by 60
“However, unlike Bmal1, Clock transcript levels do not alter significantly across the day in tissues and cells including macrophages [31].”
BackgroundHeipertz, E. L., Harper, J., Lopez, C. A., Fikrig, E., Hughes, M. E., & Walker, W. E. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701677 · Cited by 56
“(7) identified multiple genes in TLR signaling pathways that are modulated by circadian rhythms, and some of these”
BackgroundResultInfluentialThe Role of the Body Clock in Asthma and COPD: Implication for Treatment
Krakowiak, K., & Durrington, H. J. (2018) · Pulmonary Therapy · doi:10.1007/s41030-018-0058-6 · Cited by 56
Daily oscillations in expression and responsiveness of Toll-like receptors in splenic immune cells
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“1B and 4), circadian regulation of posttranslational modifications, TLR cellular trafficking, or that various aspects of the TLR signaling pathway [21] could be under circadian control.”
BackgroundInfluentialA Pro- and Anti-inflammatory Axis Modulates the Macrophage Circadian Clock
Chen, S., Fuller, K. K., Dunlap, J., & Loros, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00867 · Cited by 55
“A positive arm, consisting of the transcription factors BMAL1 and CLOCK (24–27), drives the expression of clock-controlled genes (CCGs) and also the expression of a negative arm encompassing the protein products of Per1/Per2/Per3 and Cry1/Cry2 (28–31).”
BackgroundResultInfluentialCircadian Rhythms in Adipose Tissue Physiology
Kiehn, J., Tsang, A. H. K., Heyde, I., Leinweber, B., Kolbe, I., Leliavski, A., & Oster, H. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160017 · Cited by 64
Circadian and Sleep Metabolomics Across Species
Malik, D. M., Paschos, G. K., Sehgal, A., & Weljie, A. M. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.04.027 · Cited by 54
“For example, the mammalian circadian clock has been shown to influence immune responses [7] and time-of-day variation of inflammatory responses [8] and susceptibility to infections [9].”
BackgroundNeutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism
Crespo, M., González‐Terán, B., Nikolić, I., Mora, A., Folgueira, C., Rodríguez, E., Leiva‐Vega, L., Chocano, A. P., Fernández-Chacón, M., Ruiz-Garrido, I., et al. (2020) · eLife · doi:10.7554/elife.59258 · Cited by 54
Circadian Regulation of the Biology of Allergic Disease: Clock Disruption Can Promote Allergy
Nakao, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01237 · Cited by 53
“About 8% of genes expressed in peritoneal macrophages are rhythmically transcribed, including essential elements in LPS/TLR4 signaling (71).”
BackgroundNakazato, R., Takarada, T., Yamamoto, T. M., Hotta, S., Hinoi, E., & Yoneda, Y. (2011) · Journal of Pharmacological Sciences · doi:10.1254/jphs.11069fp · Cited by 55
The influence of regulatory T cells and diurnal hormone rhythms on T helper cell activity
Bollinger, T., Bollinger, A., Naujoks, J., Lange, T., & Solbach, W. (2010) · Immunology · doi:10.1111/j.1365-2567.2010.03320.x · Cited by 52
Circadian rhythms, Neuroinflammation and Oxidative Stress in the Story of Parkinson’s Disease
Vallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2020) · Cells · doi:10.3390/cells9020314 · Cited by 55
“In macrophages, Per2 mRNA rhythms act as inverse phase to Bmal1 [122].”
BackgroundThe Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis
Ball, L. J., Palesh, O. G., & Kriegsfeld, L. J. (2016) · Endocrine Reviews · doi:10.1210/er.2015-1133 · Cited by 54
Wang, X., Reece, S. W., Scott, M. R. V., & Brown, J. M. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.09.007 · Cited by 54
“Circadian clock genes are expressed in a number of immune cells including natural killer (NK) cells (Arjona and Sarkar, 2008, 2006, 2005), macrophages (Keller et al., 2009), and T-cell subsets (Dimitrov et al., 2009).”
InfluentialThe Complex Interplay of Parasites, Their Hosts, and Circadian Clocks
Cabral, P. C., Olivier, M., & Cermakian, N. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00425 · Cited by 51
Shen, Y., Xu, L., Tang, X., Lin, C., Dong, Y., Song, X., Qian, R., & Guo, D. (2021) · BMC Medical Genomics · doi:10.1186/s12920-021-00991-2 · Cited by 51
“Many types of immune cells have been proven to possess intrinsic clocks, and these cell types include macrophages [29], monocytes [30], neutrophils [31], natural killer (NK) cells [32], mast cells and eosinophils [33].”
BackgroundEndotoxin Disrupts Circadian Rhythms in Macrophages via Reactive Oxygen Species
Wang, Y., Pati, P., Xu, Y., Chen, F., Stepp, D. W., Huo, Y., Rudic, R. D., & Fulton, D. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0155075 · Cited by 51
“from immune cells and severity of endotoxic shock depends on the time of day that LPS is administered [24, 32] and that LPS can suppress the expression of circadian clock genes [33, 34].”
BackgroundResultInfluentialSystems and Circuits Linking Chronic Pain and Circadian Rhythms
Warfield, A. E., Prather, J. F., & Todd, W. D. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.705173 · Cited by 49
“Circadian rhythms have been shown in peripheral macrophages and monocytes (Boivin et al., 2003; Hayashi et al., 2007; Keller et al., 2009), T cells (Bollinger et al., 2011), NK cells (Arjona and Sarkar, 2006), and dendritic cells and B cells (Silver et al., 2012).”
BackgroundCardioprotective Properties of Phenolic Compounds: A Role for Biological Rhythms
Torres‐Fuentes, C., Suárez, M., Aragonès, G., Mulero, M., Ávila‐Román, J., Arola‐Arnal, A., Salvadó, M. J., Arola, L., Bravo, F. I., & Muguerza, B. (2022) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100990 · Cited by 52
Melatonin regulates the rhythmic migration of neutrophils in live zebrafish
Ren, D., Li, Y., Hu, B., Wang, H., & Hu, B. (2015) · Journal of Pineal Research · doi:10.1111/jpi.12230 · Cited by 48
“Intriguingly, pro-inflammatory cytokines such as TNF-a and IL-6 were found to be significantly upregulated in macrophages and fibroblasts of the double Cry1 / ; Cry2 / mice [16, 20], suggesting a regulatory role of the circadian clock role in inflammatory responses.”
BackgroundEnvironmental Circadian Disruption Increases Stroke Severity and Dysregulates Immune Response
Ramsey, A. M., Stowie, A. C., Castañón‐Cervantes, O., & Davidson, A. J. (2020) · Journal of Biological Rhythms · doi:10.1177/0748730420929450 · Cited by 48
“Isolated immune cells exhibit rhythms in response to endotoxins (Boivin et al., 2003; Keller et al., 2009; Bollinger et al., 2011).”
BackgroundChronotherapy of Non-Steroidal Anti-Inflammatory Drugs May Enhance Postoperative Recovery
Al‐Waeli, H., Nicolau, B. F., Stone, L. S., Nada, L. A., Gao, Q., Abdallah, M., Abdulkader, E., Suzuki, M., Mansour, A., Subaie, A. E. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-019-57215-y · Cited by 52
Obstructive Sleep Apnea, Circadian Clock Disruption, and Metabolic Consequences
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“Additionally, TNFα and IL-6 exhibit daily rhythmicity, proving the relationship between cytokines and the core clock [230].”
Hazan, G., Duek, O. A., Alapi, H., Mok, H., Ganninger, A., Ostendorf, E., Gierasch, C. M., Chodick, G., Greenberg, D. A., & Haspel, J. A. (2023) · Journal of Clinical Investigation · doi:10.1172/jci167339 · Cited by 48
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“[21] Splenocytes from mice, isolated at various times of the day, were challenged with LPS Circadian rhythmicity of TNF-α and IL-6 secretion was found.”
BackgroundMethodLech, K., Liu, F., Ackermann, K., Revell, V. L., Lao, Ó., Skene, D. J., & Kayser, M. (2015) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2015.12.008 · Cited by 49
The role of the hypothalamic-pituitary-adrenal axis in modulating seasonal changes in immunity
Pierre, K. K., Schlesinger, N., & Androulakis, I. P. (2016) · Physiological Genomics · doi:10.1152/physiolgenomics.00006.2016 · Cited by 50
“These diurnal variations in immune function are modulated by autonomous cellular oscillators known as peripheral clock genes (PCGs).”
BackgroundInfluentialBennardo, M., Alibhai, F. J., Tsimakouridze, E. V., Chinnappareddy, N., Podobed, P. S., Reitz, C. J., Pyle, W. G., Simpson, J. A., & Martino, T. A. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00200.2016 · Cited by 48
“pneumonia (15), Coxsackie B virus (14), or lipopolysaccharideinduced endotoxic shock (21, 32).”
BackgroundCircadian regulation of astrocyte function: implications for Alzheimer’s disease
McKee, C. A., Lananna, B. V., & Musiek, E. S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03314-y · Cited by 49
Sleep and Fatigue in IBD: an Unrecognized but Important Extra-intestinal Manifestation
Canakis, A., & Qazi, T. (2020) · Current Gastroenterology Reports · doi:10.1007/s11894-020-0746-x · Cited by 47
“Importantly, regulatory sites include intestinal epithelial cells and macrophages [16, 17].”
BackgroundNakanishi, H., Ni, J., Nonaka, S., & Hayashi, Y. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104905 · Cited by 49
Agorastos, A., Hauger, R. L., Barkauskas, D. A., Lerman, I. R., Moeller‐Bertram, T., Snijders, C., Haji, U., Patel, P. M., Geracioti, T. D., Chrousos, G. P., et al. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.09.009 · Cited by 48
Guido, M. E., Monjes, N. M., Wagner, P. M., & Salvador, G. A. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02595-4 · Cited by 46
Mohebbi, I., Shateri, K., & Seyedmohammadzad, M. (2012) · International Journal of Occupational Medicine and Environmental Health · doi:10.2478/s13382-012-0051-5 · Cited by 50
Stress as a Normal Cue in the Symbiotic Environment
Schwartzman, J. A., & Ruby, E. G. (2016) · Trends in Microbiology · doi:10.1016/j.tim.2016.02.012 · Cited by 46
“Beneficial microbes in plants and animals form symbioses in the context of host biological rhythms and, in some cases, actually contribute to entraining these rhythms [82–87].”
BackgroundCircadian Disruption in Critical Illness
Jobanputra, A. M., Scharf, M. T., Androulakis, I. P., & Sunderram, J. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00820 · Cited by 45
“were among the first to convincingly demonstrate that macrophages in diverse mouse tissues contain autonomous circadian clocks conferring to tissues the ability to sense danger signals, lipopolysaccharides (LPS), in a time-of-day dependent manner (14).”
BackgroundPatel, J. S., Woo, Y., Draper, A., Jansen, C. S., Carlisle, J. W., Innominato, P. F., Lévi, F., Dhabaan, L., Master, V. A., Bilen, M. A., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008011 · Cited by 48
Glial Cell Regulation of Rhythmic Behavior
Jackson, F. R., Ng, F., Sengupta, S., You, S., & Huang, Y. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2014.10.016 · Cited by 44
“It is known that TNFα and other cytokines are released from immune cells according to a circadian rhythm (Keller et al., 2009) in response to an inflammatory insult, but it has not been shown 339 Glial Cell Regulation of Rhythmic Behavior ARTICLE IN PRESS”
InfluentialThe importance of determining circadian parameters in pharmacological studies
Gaspar, L. S., Álvaro, A. R., Carmo‐Silva, S., Mendes, A. F., Relógio, A., & Cavadas, C. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14712 · Cited by 53
“, 2005), bloodmonocytes (Keller et al., 2009), hair follicle cells (Akashi et al.”
BackgroundKnitting Up the Raveled Sleave of Care
Yang, G., Paschos, G. K., Curtis, A. M., Musiek, E. S., McLoughlin, S. C., & FitzGerald, G. A. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3007225 · Cited by 45
“Mouse B cells, T cells, macrophages, and natural killer cells contain cell-autonomous clocks (50), and the lethality from injected LPS— which causes septic shock—is greatest when the challenge occurs during transition into the activity phase (51), correlating with an enhanced production of IL-6 and TNFa from macrophag…”
BackgroundChen, M., Hsu, J.-W., Huang, K., Tsai, S., Su, T., Li, C., Lin, W.-C., Tu, P., & Bai, Y. (2020) · CNS Spectrums · doi:10.1017/s1092852920001534 · Cited by 44
“Third, previous studies suggested the diurnal variations in the levels of proinflammatory cytokines, including TNF-α.(35,36) The blood samples of our patients were not collected at the same time (between 9 am and 5 pm at the work time), which may confound our findings.”
Yu, D., Fang, X., Xu, Y., Xiao, H., Huang, T., Zhang, Y., Ge, Y., Li, Y., Zong, L., & Gao, J. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.04.035 · Cited by 44
Regulatory T cells confer a circadian signature on inflammatory arthritis
Hand, L. E., Gray, K. J., Dickson, S. H., Simpkins, D., Ray, D. W., Konkel, J. E., Hepworth, M. R., & Gibbs, J. E. (2020) · Nature Communications · doi:10.1038/s41467-020-15525-0 · Cited by 44
Time of day as a critical variable in biology
Nelson, R. J., Bumgarner, J. R., Liu, J. A., Love, J. A., Meléndez‐Fernández, O. H., Becker‐Krail, D. D., Walker, W. H., Walton, J. C., DeVries, A. C., & Prendergast, B. J. (2022) · BMC Biology · doi:10.1186/s12915-022-01333-z · Cited by 45
“For example, daily oscillations in gene expression, surface marker expression, cytokine secretion, proliferation, trafficking, effector function, and responsiveness have been described for many immune cells [51, 52]; a proposed adaptive explanation is that circadian regulation of immunity maximizes the benefits of imm…”
BackgroundThe diverse roles of the circadian clock in cancer
Fortin, B. M., Mahieu, A. L., Fellows, R. C., Kang, Y., Lewis, A. N., Ead, A., Lamia, K. A., Cao, Y., Pannunzio, N. R., & Masri, S. (2025) · Nature Cancer · doi:10.1038/s43018-025-00981-8 · Cited by 49
Paladino, N., Leone, M. J., Plano, S. A., & Golombek, D. A. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.04.015 · Cited by 43
“In addition, key immunemechanisms might be intrinsically rhythmic, as recently suggested for spleen, lymph nodes and peritoneal macrophages (Davidson et al., 2009; Keller et al., 2009).”
BackgroundTime-Restricted Feeding Alters the Innate Immune Response to Bacterial Endotoxin
Cissé, Y. M., Borniger, J. C., Lemanski, E. A., Walker, W. H., & Nelson, R. J. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1701136 · Cited by 43
“Diurnal variation in IL-6 and TNF-a responses to endotoxin are driven by macrophage circadian rhythms, with maximal responses during the late light/early dark phase (2).”
BackgroundOrman, M. A., Nguyen, T. T., Ierapetritou, M., Francois Berthiaume, B., & Androulakis, I. P. (2011) · Cytokine · doi:10.1016/j.cyto.2011.05.010 · Cited by 45
“Moreover, cyclic fluctuations (or circadian rhythm) in cytokine expressions, which affects the inflammatory response of the body [62], can display 24 h period and even persist in the absence of external timing information [63].”
BackgroundTime of day determines postexercise metabolism in mouse adipose tissue
Pendergrast, L. A., Lundell, L. S., Ehrlich, A. M., Ashcroft, S. P., Schönke, M., Basse, A. L., Krook, A., Treebak, J. T., Dollet, L., & Zierath, J. R. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2218510120 · Cited by 42
“For instance, macrophages show circadian rhythmicity in cytokine expression (49); thus, paracrine effects of cell populations within heterogenous tissues such as adipose may become relevant when considering time-of-day effects.”
Stroke in the Time of Circadian Medicine
Mergenthaler, P., Balami, J. S., Neuhaus, A. A., Mottahedin, A., Albers, G. W., Rothwell, P. M., Saver, J. L., Young, M. E., & Buchan, A. M. (2024) · Circulation Research · doi:10.1161/circresaha.124.323508 · Cited by 43
Lazado, C. C., Lund, I., Pedersen, P. B., & Nguyen, H. Q. (2015) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2015.10.037 · Cited by 42
Circadian rhythms in leukocyte trafficking
Druzd, D., de Juan, A., & Scheiermann, C. (2014) · Seminars in Immunopathology · doi:10.1007/s00281-013-0414-4 · Cited by 43
Amidfar, M., Garcez, M. L., & Kim, Y. (2023) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110721 · Cited by 43
Leone, M. J., Marpegán, L., Duhart, J. M., & Golombek, D. A. (2012) · Chronobiology International · doi:10.3109/07420528.2012.682681 · Cited by 42
“The response to an immune challenge is also time dependent, both at the cellular and the systemic level (Halberg et al., 1960; Hrushesky et al., 1994; Keller et al., 2009; Marpegan et al., 2009), and circadian disruption can lead to altered immunological response (Castanon-Cervantes et al., 2010).”
BackgroundInfluentialLipid droplets, autophagy, and ageing: A cell-specific tale
Maestri, A., Garagnani, P., Pedrelli, M., Hagberg, C. E., Parini, P., & Ehrenborg, E. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102194 · Cited by 45
“Circadian rhythm governs and regulates leukocyte trafficking, immunosurveillance and immune responses to pathogens (He et al., 2018; Keller et al., 2009).”
Mavroudis, P. D., Corbett, S., Calvano, S. E., & Androulakis, I. P. (2014) · Mathematical Biosciences · doi:10.1016/j.mbs.2014.10.006 · Cited by 42
“P A A uthor M anuscript is also regulated by PCGs network through Per/Cry mRNA.”
InfluentialDalvin, L. A., & Fautsch, M. P. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-16449 · Cited by 37
Hormesis mediates dose-sensitive shifts in macrophage activation patterns
Calabrese, E. J., Giordano, J. J., Kozumbo, W. J., Leak, R. K., & Bhatia, T. N. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.10.010 · Cited by 44
Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication
Borrmann, H., Davies, R., Dickinson, M. G., Pedroza‐Pacheco, I., Schilling, M., Vaughan-Jackson, A., Magri, A., James, W., Balfe, P., Borrow, P., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-70170-3 · Cited by 41
Modulation of mammalian circadian rhythms by tumor necrosis factor-α
Paladino, N., Fedele, M. L. M., Duhart, J. M., Marpegán, L., & Golombek, D. A. (2014) · Chronobiology International · doi:10.3109/07420528.2014.886588 · Cited by 43
“In addition, key immune mechanisms might be intrinsically rhythmic, as recently suggested for spleen, lymph nodes and peritoneal macrophages (Bollinger et al., 2011; Keller et al., 2009).”
BackgroundPeripheral circadian clocks are diversely affected by adrenalectomy
Soták, M., Bryndová, J., Ergang, P., Vagnerová, K., Kvapilová, P., Vodička, M., Pácha, J., & Sumová, A. (2016) · Chronobiology International · doi:10.3109/07420528.2016.1161643 · Cited by 40
“The system that governs daily variations is composed of a master clock, which is a pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN), and peripheral clocks that are found in most cells and organs (Keller et al., 2009; Mohawk et al., 2012; Sládek et al., 2007; Su et al., 2015).”
BackgroundA wheel of time: the circadian clock, nuclear receptors, and physiology: Figure 1.Preprint
Yang, X. (2010) · Genes & Development · doi:10.1101/gad.1920710 · Cited by 43
“Recent studies provide compelling evidence that these diurnal variations are ascribed to intrinsic clockworks in immune cells (Arjona and Sarkar 2006; Keller et al. 2009).”
BackgroundFellows, R. C., Chun, S. K., Larson, N., Fortin, B. M., Mahieu, A. L., Song, W. A., Seldin, M. M., Pannunzio, N. R., & Masri, S. (2024) · Science Advances · doi:10.1126/sciadv.ado1458 · Cited by 42
O’Donnell, A. J., Mideo, N., & Reece, S. E. (2013) · Malaria Journal · doi:10.1186/1475-2875-12-372 · Cited by 40
“For example, given the circadian periodicity of macrophage activity [17], parasites injected in the evening were likely to encounter peritoneal macrophages in the peak of their protective activity.”
Emotion: the Self-regulatory Sense
Kauffman, K. P. (2014) · Global Advances in Health and Medicine · doi:10.7453/gahmj.2013.058 · Cited by 48
Guerrero‐Vargas, N. N., Guzmán‐Ruiz, M. A., Fuentes, R., García, J., Salgado‐Delgado, R., Basualdo, M. D. C., Escobar, C., Markus, R. P., & Buijs, R. M. (2015) · Journal of Biological Rhythms · doi:10.1177/0748730415586482 · Cited by 43
“…partly responsible for the increased inflammatory response, because their influence in immune functions is well documented (Arjona and Sarkar, 2006a, 2006b; Daynes and Jones, 2002; Gibbs et al., 2012; Keller et al., 2009; Liu et al., 2006; Logan et al., 2013; Oishi et al., 2006; Yang et al., 2012).”
BackgroundCircadian Clock and Complement Immune System—Complementary Control of Physiology and Pathology?
Shivshankar, P., Fekry, B., Eckel‐Mahan, K. L., & Wetsel, R. A. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00418 · Cited by 40
“In mice in which there is no functioning circadian clock in macrophages (Keller et al., 2009; Labrecque and Cermakian, 2015), rhythmicity in infection was eliminated (Kiessling et al.”
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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