Circadian rhythms are endogenous oscillations in organisms of ∼24 hours in length that exist in virtually all cells.
The number of circulating leukocytes in the blood oscillates in a manner according to the phase of physical activity of the organism. Generally, the peak occurs during the resting phase.
In contrast to the peak number of circulating leukocytes, leukocyte recruitment to tissues occurs preferentially during the active phase of the organism. It is mediated by the in-phase expression of cell adhesion molecules and chemokines.
The response of an organism to acute inflammatory insults exhibits circadian oscillations. This is probably due to the circadian regulation of leukocyte trafficking, of the expression of pathogen-sensitive receptors and of the phagocytic activity of leukocytes.
Chronic diseases exhibit circadian exacerbations in their symptoms or presentations, which has been linked to an exaggeration of the circadian expression of pro-inflammatory mediators.
Circadian rhythms should be taken into account when harvesting human tissue samples and in experimental settings using preclinical animal models. In addition, chronopharmacology holds great promise to provide benefits for clinical care in the future.
Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Halberg, F., Halberg, E., Barnum, C. P. & Bittner, J. J. in Photoperiodism and Related Phenomena in Plants and Animals (ed. Withrow, R. B. ) 803–878 (American Association for the Advancement of Science, 1959).
Edgar, R. S. et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485, 459–464 (2012).
Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).
Storch, K. F. et al. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83 (2002).
Arjona, A., Silver, A. C., Walker, W. E. & Fikrig, E. Immunity's fourth dimension: approaching the circadian–immune connection. Trends Immunol. 33, 607–612 (2012). This article provides a nice overview of the recent developments in the circadian immunology field.
Lange, T., Dimitrov, S. & Born, J. Effects of sleep and circadian rhythm on the human immune system. Ann. NY Acad. Sci. 1193, 48–59 (2010).
Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012). This was the first study to show a circadian rhythm in leukocyte recruitment to tissues and the implication in homeostasis and inflammation.
Keller, M. et al. A circadian clock in macrophages controls inflammatory immune responses. Proc. Natl Acad. Sci. USA 106, 21407–21412 (2009). This study describes a macrophage-intrinsic clock that drives the circadian expression of the signalling pathways involved in the response to endotoxins.
Silver, A. C., Arjona, A., Walker, W. E. & Fikrig, E. The circadian clock controls Toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36, 251–261 (2012). This paper shows that a circadian rhythm in TLR9 expression has long-term implications for immunization and adaptive immunity.
Aschoff, J. Exogenous and endogenous components in circadian rhythms. Cold Spring Harb. Symp. Quant. Biol. 25, 11–28 (1960).
Green, C. B., Takahashi, J. S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008).
Golombek, D. A. & Rosenstein, R. E. Physiology of circadian entrainment. Physiol. Rev. 90, 1063–1102 (2010).
Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).
Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).
Takahashi, J. S., Hong, H. K., Ko, C. H. & McDearmon, E. L. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nature Rev. Genet. 9, 764–775 (2008).
Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).
Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012).
O'Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature 469, 498–503 (2011).
O'Neill, J. S. et al. Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554–558 (2011).
Boivin, D. B. et al. Circadian clock genes oscillate in human peripheral blood mononuclear cells. Blood 102, 4143–4145 (2003).
Bollinger, T. et al. Circadian clocks in mouse and human CD4+ T cells. PLoS ONE 666, e29801 (2011).
Dickmeis, T. Glucocorticoids and the circadian clock. J. Endocrinol. 200, 3–22 (2009).
Elenkov, I. J., Wilder, R. L., Chrousos, G. P. & Vizi, E. S. The sympathetic nerve — an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595–638 (2000).
Le Minh, N., Damiola, F., Tronche, F., Schutz, G. & Schibler, U. Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. EMBO J. 20, 7128–7136 (2001).
Haus, E. & Smolensky, M. H. Biologic rhythms in the immune system. Chronobiol. Int. 16, 581–622 (1999).
Dimitrov, S. et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 113, 5134–5143 (2009).
Haus, E., Lakatua, D. J., Swoyer, J. & Sackett-Lundeen, L. Chronobiology in hematology and immunology. Am. J. Anat. 168, 467–517 (1983).
Mendez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008). This was the first study to show that HSCs are released into the blood from the bone marrow in a circadian manner dependent on CXCL12.
Lucas, D., Battista, M., Shi, P. A., Isola, L. & Frenette, P. S. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3, 364–366 (2008). This paper describes circadian oscillations in the yield of HSCs harvested from human blood.
Cardinali, D. P., Brusco, L. I., Selgas, L. & Esquifino, A. I. Diurnal rhythms in ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats during Freund's adjuvant-induced arthritis. Brain Res. 789, 283–292 (1998).
Litvinenko, G. I. et al. Circadian dynamics of cell composition of the thymus and lymph nodes in mice normally, under conditions of permanent illumination, and after melatonin injection. Bull. Exp. Biol. Med. 140, 213–216 (2005).
Feigin, R. D., Middelkamp, J. N. & Reed, C. Circadian rhythmicity in susceptibility of mice to sublethal Coxsackie B3 infection. Nature New Biol. 240, 57–58 (1972).
Feigin, R. D., San Joaquin, V. H., Haymond, M. W. & Wyatt, R. G. Daily periodicity of susceptibility of mice to pneumococcal infection. Nature 224, 379–380 (1969).
Halberg, F., Johnson, E. A., Brown, B. W. & Bittner, J. J. Susceptibility rhythm to E. coli endotoxin and bioassay. Proc. Soc. Exp. Biol. Med. 103, 142–144 (1960).
House, S. D., Ruch, S., Koscienski, W. F., Rocholl, C. W. & Moldow, R. L. Effects of the circadian rhythm of corticosteroids on leukocyte–endothelium interactions in the AM and PM. Life Sci. 60, 2023–2034 (1997).
Hrushesky, W. J., Langevin, T., Kim, Y. J. & Wood, P. A. Circadian dynamics of tumor necrosis factor α (cachectin) lethality. J. Exp. Med. 180, 1059–1065 (1994).
Shackelford, P. G. & Feigin, R. D. Periodicity of susceptibility to pneumococcal infection: influence of light and adrenocortical secretions. Science 182, 285–287 (1973).
Gibbs, J. E. et al. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc. Natl Acad. Sci. USA 109, 582–587 (2012).
Arjona, A. & Sarkar, D. K. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J. Immunol. 174, 7618–7624 (2005).
Hriscu, M. L. Modulatory factors of circadian phagocytic activity. Ann. NY Acad. Sci. 1057, 403–430 (2005).
Logan, R. W., Arjona, A. & Sarkar, D. K. Role of sympathetic nervous system in the entrainment of circadian natural-killer cell function. Brain Behav. Immun. 25, 101–109 (2011).
Lazzaro, B. P., Sceurman, B. K. & Clark, A. G. Genetic basis of natural variation in D. melanogaster antibacterial immunity. Science 303, 1873–1876 (2004).
Lee, J. E. & Edery, I. Circadian regulation in the ability of Drosophila to combat pathogenic infections. Curr. Biol. 18, 195–199 (2008).
McDonald, M. J. & Rosbash, M. Microarray analysis and organization of circadian gene expression in Drosophila. Cell 107, 567–578 (2001).
Roden, L. C. & Ingle, R. A. Lights, rhythms, infection: the role of light and the circadian clock in determining the outcome of plant–pathogen interactions. Plant Cell 21, 2546–2552 (2009).
Shirasu-Hiza, M. M., Dionne, M. S., Pham, L. N., Ayres, J. S. & Schneider, D. S. Interactions between circadian rhythm and immunity in Drosophila melanogaster. Curr. Biol. 17, R353–R355 (2007).
Stone, E. F. et al. The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. PLoS Pathog. 866, e1002445 (2012).
Wang, W. et al. Timing of plant immune responses by a central circadian regulator. Nature 470, 110–114 (2011).
Auvil-Novak, S. E., Novak, R. D. & el Sanadi, N. Twenty-four-hour pattern in emergency department presentation for sickle cell vaso-occlusive pain crisis. Chronobiol. Int. 13, 449–456 (1996).
Cutolo, M. Chronobiology and the treatment of rheumatoid arthritis. Curr. Opin. Rheumatol. 24, 312–318 (2012).
Gupta, A. & Shetty, H. Circadian variation in stroke — a prospective hospital-based study. Int. J. Clin. Pract. 59, 1272–1275 (2005).
Muller, J. E. et al. Circadian variation in the frequency of onset of acute myocardial infarction. N. Engl. J. Med. 313, 1315–1322 (1985).
Panzer, S. E., Dodge, A. M., Kelly, E. A. & Jarjour, N. N. Circadian variation of sputum inflammatory cells in mild asthma. J. Allergy Clin. Immunol. 111, 308–312 (2003).
Smolensky, M. H., Lemmer, B. & Reinberg, A. E. Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma. Adv. Drug Deliv. Rev. 59, 852–882 (2007).
Jeyaraj, D. et al. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483, 96–99 (2012).
Marfella, R. et al. Morning blood pressure surge as a destabilizing factor of atherosclerotic plaque: role of ubiquitin–proteasome activity. Hypertension 49, 784–791 (2007).
Shichita, T. et al. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nature Med. 18, 911–917 (2012).
Suarez-Barrientos, A. et al. Circadian variations of infarct size in acute myocardial infarction. Heart 97, 970–976 (2011).
Coller, B. S. Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene? Arterioscler. Thromb. Vasc. Biol. 25, 658–670 (2005).
Frenette, P. S. & Atweh, G. F. Sickle cell disease: old discoveries, new concepts, and future promise. J. Clin. Invest. 117, 850–858 (2007).
Turhan, A., Weiss, L. A., Mohandas, N., Coller, B. S. & Frenette, P. S. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc. Natl Acad. Sci. USA 99, 3047–3051 (2002).
Narasimamurthy, R. et al. Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc. Natl Acad. Sci. USA 109, 12662–12667 (2012).
Fu, L., Pelicano, H., Liu, J., Huang, P. & Lee, C. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41–50 (2002).
Janich, P. et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 480, 209–214 (2011).
Taniguchi, H. et al. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res. 69, 8447–8454 (2009).
Filipski, E. et al. Effects of chronic jet lag on tumor progression in mice. Cancer Res. 64, 7879–7885 (2004).
Harrington, M. Location, location, location: important for jet-lagged circadian loops. J. Clin. Invest. 120, 2265–2267 (2010).
Knutsson, A. et al. Breast cancer among shift workers: results of the WOLF longitudinal cohort study. Scand. J. Work Environ. Health 24 Sep 2012 (doi:10.5271/sjweh.3323).
Carlson, D. E. & Chiu, W. C. The absence of circadian cues during recovery from sepsis modifies pituitary-adrenocortical function and impairs survival. Shock 29, 127–132 (2008).
Beauchamp, D. & Labrecque, G. Chronobiology and chronotoxicology of antibiotics and aminoglycosides. Adv. Drug Deliv. Rev. 59, 896–903 (2007).
Gorbacheva, V. Y. et al. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc. Natl Acad. Sci. USA 102, 3407–3412 (2005).
Levi, F. & Schibler, U. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47, 593–628 (2007).
Zmrzljak, U. P. & Rozman, D. Circadian regulation of the hepatic endobiotic and xenobitoic detoxification pathways: the time matters. Chem. Res. Toxicol. 25, 811–824 (2012).
Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).
Our work was supported by grants from the US National Institutes of Health (R01 HL097700, DK056638, HL097819, HL116340 and HL069438) to P.S.F., from the German Academic Exchange Service (DAAD) to C.S. and from the Japan Society for the Promotion of Science to Y.K.
The authors declare no competing financial interests.
- Sympathetic nerves
Nerves that belong to the sympathetic nervous system (SNS), which together with the parasympathetic nervous system makes up the autonomic nervous system. The SNS is under involuntary control and, among other functions, acts to mobilize the body's fight-or-flight response.
(German for 'time giver'). An environmental cue, such as light, food or temperature, that synchronizes the endogenous rhythm of an organism to the Earth's 24-hour light–dark cycle.
- Rest–activity cycle
A species-specific rhythm determined by diurnal (in humans) or nocturnal (in rodents) periods of activity followed by times of rest.
- Retinohypothalamic tract
A photic input pathway that connects photosensitive retinal ganglion cells directly to the suprachiasmatic nuclei of the hypothalamus.
- Suprachiasmatic nuclei
A pair of nuclei (each consisting of approximately 10,000 highly interconnected neurons) that are located in a small region of the hypothalamus, above the optic chiasm, from where they receive environmental light input through the retinohypothalamic tract.
- Hypothalamic–pituitary–adrenal axis
(HPA axis). The HPA axis consists of a complex set of input and feedback mechanisms between the hypothalamus, the pituitary gland and the adrenal gland. It is a major part of the neuroendocrine system.
A pattern that occurs during the day, in contrast to nocturnal.
The time at which the peak of a rhythm occurs.
About this article
Cite this article
Scheiermann, C., Kunisaki, Y. & Frenette, P. Circadian control of the immune system. Nat Rev Immunol 13, 190–198 (2013) doi:10.1038/nri3386
Disruption of circadian rhythm by alternating light‐dark cycles aggravates atherosclerosis development in APOE*3‐Leiden.CETP mice
Journal of Pineal Research (2020)
Frontiers in Cardiovascular Medicine (2019)
Clinical Gastroenterology and Hepatology (2019)