Review Article | Published:

Clocking in to immunity

Nature Reviews Immunologyvolume 18pages423437 (2018) | Download Citation

Abstract

Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Manchester Biological Timing: https://www.bmh.manchester.ac.uk/research/biological-timing/

Loudon Laboratory: http://www.manchester.ac.uk/research/Andrew.loudon/personaldetails

Scheiermann Laboratory: http://scheiermannlab.de/

Gibbs Laboratory: https://www.research.manchester.ac.uk/portal/Julie.Gibbs.html

References

  1. 1.

    Edgar, R. S. et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485, 459–464 (2012).

  2. 2.

    Pittendrigh, C. S. Temporal organization: reflections of a Darwinian clock-watcher. Annu. Rev. Physiol. 55, 16–54 (1993).

  3. 3.

    Brown, T. M. & Piggins, H. D. Electrophysiology of the suprachiasmatic circadian clock. Prog. Neurobiol. 82, 229–255 (2007).

  4. 4.

    Brancaccio, M. et al. Network-mediated encoding of circadian time: the suprachiasmatic nucleus (SCN) from genes to neurons to circuits, and back. J. Neurosci. 34, 15192–15199 (2014).

  5. 5.

    Herzog, E. D., Hermanstyne, T., Smyllie, N. J. & Hastings, M. H. Regulating the suprachiasmatic nucleus (SCN) circadian clockwork: interplay between cell-autonomous and circuit-level mechanisms. Cold Spring Harb. Perspect. Biol. 9, a027706 (2017).

  6. 6.

    Buijs, F. N. et al. The circadian system: a regulatory feedback network of periphery and brain. Physiology 31, 170–181 (2016).

  7. 7.

    Dumbell, R., Matveeva, O. & Oster, H. Circadian clocks, stress, and immunity. Front. Endocrinol. 7, 37 (2016).

  8. 8.

    Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510 (2016).

  9. 9.

    Bass, J. & Lazar, M. A. Circadian time signatures of fitness and disease. Science 354, 994–999 (2016).

  10. 10.

    Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).

  11. 11.

    Spoelstra, K., Wikelski, M., Daan, S., Loudon, A. S. & Hau, M. Natural selection against a circadian clock gene mutation in mice. Proc. Natl Acad. Sci. USA 113, 686–691 (2016).

  12. 12.

    McHill, A. W. & Wright, K. P. Jr. Role of sleep and circadian disruption on energy expenditure and in metabolic predisposition to human obesity and metabolic disease. Obes. Rev. 18 (Suppl. 1), 15–24 (2017).

  13. 13.

    Qian, J. & Scheer, F. A. Circadian system and glucose metabolism: implications for physiology and disease. Trends Endocrinol. Metab. 27, 282–293 (2016).

  14. 14.

    Reitz, C. J. & Martino, T. A. Disruption of circadian rhythms and sleep on critical illness and the impact on cardiovascular events. Curr. Pharm. Des. 21, 3505–3511 (2015).

  15. 15.

    Yuan, X. et al. Night shift work increases the risks of multiple primary cancers in women: a systematic review and meta-analysis of 61 articles. Cancer Epidemiol. Biomarkers Prev. 27, 25–40 (2018).

  16. 16.

    Berenbaum, F. & Meng, Q. J. The brain-joint axis in osteoarthritis: nerves, circadian clocks and beyond. Nat. Rev. Rheumatol. 12, 508–516 (2016).

  17. 17.

    Cutolo, M. Rheumatoid arthritis: circadian and circannual rhythms in RA. Nat. Rev. Rheumatol. 7, 500–502 (2011).

  18. 18.

    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).

  19. 19.

    Curtis, A. M., Bellet, M. M., Sassone-Corsi, P. & O’Neill, L. A. Circadian clock proteins and immunity. Immunity 40, 178–186 (2014).

  20. 20.

    Labrecque, N. & Cermakian, N. Circadian clocks in the immune system. J. Biol. Rhythms 30, 277–290 (2015).

  21. 21.

    Man, K., Loudon, A. & Chawla, A. Immunity around the clock. Science 354, 999–1003 (2016).

  22. 22.

    Scheiermann, C., Kunisaki, Y. & Frenette, P. S. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190–198 (2013).

  23. 23.

    Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science 341, 1483–1488 (2013). This paper shows that oscillations in the number of inflammatory monocytes in tissues are driven by the myeloid cell clock.

  24. 24.

    Keller, M. et al. A circadian clock in macrophages controls inflammatory immune responses. Proc. Natl Acad. Sci. USA 106, 21407–21412 (2009).

  25. 25.

    Silver, A. C., Arjona, A., Hughes, M. E., Nitabach, M. N. & Fikrig, E. Circadian expression of clock genes in mouse macrophages, dendritic cells, and B cells. Brain Behav. Immun. 26, 407–413 (2012).

  26. 26.

    Wang, X., Reece, S. P., Van Scott, M. R. & Brown, J. M. A circadian clock in murine bone marrow-derived mast cells modulates IgE-dependent activation in vitro. Brain Behav. Immun. 25, 127–134 (2011).

  27. 27.

    Baumann, A. et al. The circadian clock is functional in eosinophils and mast cells. Immunology 140, 465–474 (2013).

  28. 28.

    Ella, K., Csepanyi-Komi, R. & Kaldi, K. Circadian regulation of human peripheral neutrophils. Brain Behav. Immun. 57, 209–221 (2016).

  29. 29.

    Arjona, A. & Sarkar, D. K. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J. Immunol. 174, 7618–7624 (2005).

  30. 30.

    Oliva-Ramirez, J., Moreno-Altamirano, M. M., Pineda-Olvera, B., Cauich-Sanchez, P. & Sanchez-Garcia, F. J. Crosstalk between circadian rhythmicity, mitochondrial dynamics and macrophage bactericidal activity. Immunology 143, 490–497 (2014).

  31. 31.

    Gibbs, J. E. et al. The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc. Natl Acad. Sci. USA 109, 582–587 (2012). This article presents the first demonstration that synthetic ligands targeting a circadian clock protein modify inflammatory responses.

  32. 32.

    Nakamura, Y., Ishimaru, K., Shibata, S. & Nakao, A. Regulation of plasma histamine levels by the mast cell clock and its modulation by stress. Sci. Rep. 7, 39934 (2017).

  33. 33.

    Nakamura, Y. et al. Circadian regulation of allergic reactions by the mast cell clock in mice. J. Allergy Clin. Immunol. 133, 568–575 (2014).

  34. 34.

    Logan, R. W., Wynne, O., Levitt, D., Price, D. & Sarkar, D. K. Altered circadian expression of cytokines and cytolytic factors in splenic natural killer cells of Per1(−/−) mutant mice. J. Interferon Cytokine Res. 33, 108–114 (2013).

  35. 35.

    Logan, R. W. et al. Chronic shift-lag alters the circadian clock of NK cells and promotes lung cancer growth in rats. J. Immunol. 188, 2583–2591 (2012).

  36. 36.

    Lam, M. T. et al. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498, 511–515 (2013).

  37. 37.

    Sato, S. et al. A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression. J. Immunol. 192, 407–417 (2014).

  38. 38.

    Narasimamurthy, R. et al. Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc. Natl Acad. Sci. USA 109, 12662–12667 (2012).

  39. 39.

    Born, J., Lange, T., Hansen, K., Molle, M. & Fehm, H. L. Effects of sleep and circadian rhythm on human circulating immune cells. J. Immunol. 158, 4454–4464 (1997).

  40. 40.

    Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).

  41. 41.

    Prendergast, B. J. et al. Impaired leukocyte trafficking and skin inflammatory responses in hamsters lacking a functional circadian system. Brain Behav. Immun. 32, 94–104 (2013).

  42. 42.

    Haspel, J. A. et al. Circadian rhythm reprogramming during lung inflammation. Nat. Commun. 5, 4753 (2014).

  43. 43.

    Gibbs, J. et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat. Med. 20, 919–926 (2014). This paper shows circadian regulation of neutrophil influx via rhythmic inhibition of chemoattractant production by bronchial epithelial cells in the lung.

  44. 44.

    Kiessling, S. et al. The circadian clock in immune cells controls the magnitude of Leishmania parasite infection. Sci. Rep. 7, 10892 (2017).

  45. 45.

    Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153, 1025–1035 (2013). This study describes how rhythmic homing of aged neutrophils generates homeostatic cues that trigger release of haematopoietic stem cells from the bone marrow.

  46. 46.

    Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

  47. 47.

    Chong, S. Z. et al. CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J. Exp. Med. 213, 2293–2314 (2016).

  48. 48.

    Bellet, M. M. et al. Circadian clock regulates the host response to Salmonella. Proc. Natl Acad. Sci. USA 110, 9897–9902 (2013).

  49. 49.

    Rijo-Ferreira, F., Pinto-Neves, D., Barbosa-Morais, N. L., Takahashi, J. S. & Figueiredo, L. M. Trypanosoma brucei metabolism is under circadian control. Nat. Microbiol. 2, 17032 (2017).

  50. 50.

    Majumdar, T., Dhar, J., Patel, S., Kondratov, R. & Barik, S. Circadian transcription factor BMAL1 regulates innate immunity against select RNA viruses. Innate Immun. 23, 147–154 (2017).

  51. 51.

    Edgar, R. S. et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proc. Natl Acad. Sci. USA 113, 10085–10090 (2016).

  52. 52.

    Fernandes, G., Halberg, F., Yunis, E. J. & Good, R. A. Circadian rhythmic plaque-forming cell response of spleens from mice immunized with SRBC. J. Immunol. 117, 962–966 (1976).

  53. 53.

    Kaplan, M. S. et al. Circadian rhythm of stimulated lymphocyte blastogenesis. A 24 h cycle in the mixed leukocyte culture reaction and with SKSD stimulation. J. Allergy Clin. Immunol. 58, 180–189 (1976).

  54. 54.

    Druzd, D. et al. Lymphocyte circadian clocks control lymph node trafficking and adaptive immune responses. Immunity 46, 120–132 (2017). This study shows dynamic regulation of lymphocyte numbers in blood, lymph node and lymph, driven by rhythmic expression of migration and egress factors.

  55. 55.

    Hemmers, S. & Rudensky, A. Y. The cell-intrinsic circadian clock is dispensable for lymphocyte differentiation and function. Cell Rep. 11, 1339–1349 (2015).

  56. 56.

    Bollinger, T. et al. Circadian clocks in mouse and human CD4 + T cells. PLoS ONE 6, e29801 (2011).

  57. 57.

    Sun, Y. et al. MOP3, a component of the molecular clock, regulates the development of B cells. Immunology 119, 451–460 (2006).

  58. 58.

    Yu, X. et al. TH17 cell differentiation is regulated by the circadian clock. Science 342, 727–730 (2013).

  59. 59.

    Yu, X. et al. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. eLife 3, e04406 (2014).

  60. 60.

    Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013).

  61. 61.

    Farez, M. F. et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162, 1338–1352 (2015).

  62. 62.

    Martinez-Llordella, M. et al. CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4 + T cell response. J. Exp. Med. 210, 1603–1619 (2013).

  63. 63.

    Kreslavsky, T. et al. Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells. Nat. Immunol. 18, 442–455 (2017).

  64. 64.

    Besedovsky, L., Born, J. & Lange, T. Endogenous glucocorticoid receptor signaling drives rhythmic changes in human T-cell subset numbers and the expression of the chemokine receptor CXCR4. FASEB J. 28, 67–75 (2014).

  65. 65.

    Dimitrov, S. et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 113, 5134–5143 (2009).

  66. 66.

    Suzuki, K., Hayano, Y., Nakai, A., Furuta, F. & Noda, M. Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes. J. Exp. Med. 213, 2567–2574 (2016). This study shows how adrenergic tone modulates lymphocyte trafficking rhythms and humoral immune responses through β2-adrenergic receptors expressed by lymphocytes.

  67. 67.

    Zhao, Y. et al. Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice. Blood 130, 1995–2005 (2017). This is a very interesting report of cell-intrinsic phase encoding of leukocytes, driven by opposite effects of p38MAPK–MK2 signalling upon HIF1α induction and CXCR4 expression.

  68. 68.

    Shimba, A. et al. Glucocorticoids drive diurnal oscillations in T cell distribution and responses by inducing interleukin-7 receptor and CXCR4. Immunity 48, 286–298.e6 (2018). This work illustrates an immune-enhancing role of glucocorticoids via upregulation of homing receptors, promoting rhythmic T cell accumulation and heightened responses to systemic infection.

  69. 69.

    Forster, R., Davalos-Misslitz, A. C. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol. 8, 362–371 (2008).

  70. 70.

    Stein, J. V. & Nombela-Arrieta, C. Chemokine control of lymphocyte trafficking: a general overview. Immunology 116, 1–12 (2005).

  71. 71.

    Cyster, J. G. & Schwab, S. R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69–94 (2012).

  72. 72.

    Nakai, A., Hayano, Y., Furuta, F., Noda, M. & Suzuki, K. Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. J. Exp. Med. 211, 2583–2598 (2014).

  73. 73.

    Esquifino, A. I., Selgas, L., Arce, A., Maggiore, V. D. & Cardinali, D. P. Twenty-four-hour rhythms in immune responses in rat submaxillary lymph nodes and spleen: effect of cyclosporine. Brain Behav. Immun. 10, 92–102 (1996).

  74. 74.

    Fortier, E. E. et al. Circadian variation of the response of T cells to antigen. J. Immunol. 187, 6291–6300 (2011).

  75. 75.

    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).

  76. 76.

    Sutton, C. E. et al. Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease. Nat. Commun. 8, 1923 (2017). This report shows the importance of appropriate immune cell crosstalk in an EAE model, as disruption of the myeloid clock increases T H 1 and T H 17 cell responses in the central nervous system.

  77. 77.

    Long, J. E. et al. Morning vaccination enhances antibody response over afternoon vaccination: a cluster-randomised trial. Vaccine 34, 2679–2685 (2016).

  78. 78.

    Curtis, A. M. et al. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc. Natl Acad. Sci. USA 112, 7231–7236 (2015).

  79. 79.

    Huo, M. et al. Myeloid Bmal1 deletion increases monocyte recruitment and worsens atherosclerosis. FASEB J. 31, 1097–1106 (2016).

  80. 80.

    Mukherji, A., Kobiita, A., Ye, T. & Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153, 812–827 (2013).

  81. 81.

    Wang, Y. et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357, 912–916 (2017). Along with previous work from the same authors (reference 58), this study links the clock protein REV-ERBα with rhythmic expression of NFIL3, a critical regulator of both T H 17 cell differentiation and enterocyte lipid metabolism.

  82. 82.

    Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

  83. 83.

    Martin, C. et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19, 583–593 (2003).

  84. 84.

    Tanji-Matsuba, K. et al. Functional changes in aging polymorphonuclear leukocytes. Circulation 97, 91–98 (1998).

  85. 85.

    Liang, X., Bushman, F. D. & FitzGerald, G. A. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc. Natl Acad. Sci. USA 112, 10479–10484 (2015).

  86. 86.

    Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).

  87. 87.

    Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

  88. 88.

    Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).

  89. 89.

    Shackelford, P. G. & Feigin, R. D. Periodicity of susceptibility to pneumococcal infection: influence of light and adrenocortical secretions. Science 182, 285–287 (1973).

  90. 90.

    Early, J. O. & Curtis, A. M. Immunometabolism: Is it under the eye of the clock? Semin. Immunol. 28, 478–490 (2016).

  91. 91.

    Ando, N. et al. Circadian gene clock regulates psoriasis-like skin inflammation in mice. J. Invest. Dermatol. 135, 3001–3008 (2015).

  92. 92.

    Castanon-Cervantes, O. et al. Dysregulation of inflammatory responses by chronic circadian disruption. J. Immunol. 185, 5796–5805 (2010).

  93. 93.

    Pagel, R. et al. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine. FASEB J. 31, 4707–4719 (2017).

  94. 94.

    Summa, K. C. et al. Disruption of the circadian clock in mice increases intestinal permeability and promotes alcohol-induced hepatic pathology and inflammation. PLoS ONE 8, e67102 (2013).

  95. 95.

    Li, W. Q., Qureshi, A. A., Schernhammer, E. S. & Han, J. Rotating night-shift work and risk of psoriasis in US women. J. Invest. Dermatol. 133, 565–567 (2013).

  96. 96.

    Nojkov, B., Rubenstein, J. H., Chey, W. D. & Hoogerwerf, W. A. The impact of rotating shift work on the prevalence of irritable bowel syndrome in nurses. Am. J. Gastroenterol. 105, 842–847 (2010).

  97. 97.

    Cuesta, M., Boudreau, P., Dubeau-Laramee, G., Cermakian, N. & Boivin, D. B. Simulated night shift disrupts circadian rhythms of immune functions in humans. J. Immunol. 196, 2466–2475 (2016).

  98. 98.

    Durrington, H. J., Farrow, S. N., Loudon, A. S. & Ray, D. W. The circadian clock and asthma. Thorax 69, 90–92 (2014).

  99. 99.

    Olsen, N. J., Brooks, R. H. & Furst, D. Variability of immunologic and clinical features in patients with rheumatoid arthritis studied over 24 h. J. Rheumatol. 20, 940–943 (1993).

  100. 100.

    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).

  101. 101.

    Perry, M. G., Kirwan, J. R., Jessop, D. S. & Hunt, L. P. Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis. Ann. Rheum. Dis. 68, 63–68 (2009).

  102. 102.

    Takeda, N. & Maemura, K. Circadian clock and the onset of cardiovascular events. Hypertens. Res. 39, 383–390 (2016).

  103. 103.

    Culic, V. Daylight saving time transitions and acute myocardial infarction. Chronobiol. Int. 30, 662–668 (2013).

  104. 104.

    Dopico, X. C. et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat. Commun. 6, 7000 (2015).

  105. 105.

    Donaldson, G. C. & Wedzicha, J. A. The causes and consequences of seasonal variation in COPD exacerbations. Int. J. Chron. Obstruct Pulmon. Dis. 9, 1101–1110 (2014).

  106. 106.

    Spelman, T. et al. Seasonal variation of relapse rate in multiple sclerosis is latitude dependent. Ann. Neurol. 76, 880–890 (2014).

  107. 107.

    Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014). This article presents a comprehensive analysis of oscillating genes and non-coding RNAs in murine organs, highlighting the relationships between rhythmic genes, disease-associated genes and current drug targets.

  108. 108.

    Buttgereit, F. et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 371, 205–214 (2008).

  109. 109.

    Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011).

  110. 110.

    Okabe, T. et al. REV-ERBalpha influences the stability and nuclear localization of the glucocorticoid receptor. J. Cell Sci. 129, 4143–4154 (2016).

  111. 111.

    Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).

  112. 112.

    Sitaula, S., Billon, C., Kamenecka, T. M., Solt, L. A. & Burris, T. P. Suppression of atherosclerosis by synthetic REV-ERB agonist. Biochem. Biophys. Res. Commun. 460, 566–571 (2015).

  113. 113.

    Kojetin, D., Wang, Y., Kamenecka, T. M. & Burris, T. P. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem. Biol. 6, 131–134 (2011).

  114. 114.

    Gagnidze, K. et al. Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis. Proc. Natl Acad. Sci. USA 113, 5730–5735 (2016).

  115. 115.

    Hirota, T. et al. Identification of small molecule activators of cryptochrome. Science 337, 1094–1097 (2012).

  116. 116.

    Hand, L. E. et al. The circadian clock regulates inflammatory arthritis. FASEB J. 30, 3759–3770 (2016).

  117. 117.

    Partch, C. L., Green, C. B. & Takahashi, J. S. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 24, 90–99 (2014).

  118. 118.

    Guilding, C. et al. Suppressed cellular oscillations in after-hours mutant mice are associated with enhanced circadian phase-resetting. J. Physiol. 591, 1063–1080 (2013).

  119. 119.

    Meng, Q. J. et al. Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58, 78–88 (2008).

  120. 120.

    Yamaguchi, S. et al. Role of DBP in the circadian oscillatory mechanism. Mol. Cell. Biol. 20, 4773–4781 (2000).

  121. 121.

    Ueda, H. R. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192 (2005).

  122. 122.

    Fu, L. & Lee, C. C. The circadian clock: pacemaker and tumour suppressor. Nat. Rev. Cancer 3, 350–361 (2003).

  123. 123.

    Yu, E. A. & Weaver, D. R. Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging 3, 479–493 (2011).

  124. 124.

    Asher, G. & Sassone-Corsi, P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161, 84–92 (2015).

  125. 125.

    Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 485, 123–127 (2012).

  126. 126.

    Zhang, Y. et al. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348, 1488–1492 (2015).

  127. 127.

    Masri, S. et al. Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell 165, 896–909 (2016).

  128. 128.

    Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018). This study shows that agonism of REV-ERBs is specifically lethal to cancer cells via inhibition of autophagy and lipogenesis

  129. 129.

    Fonken, L. K. et al. Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain Behav. Immun. 45, 171–179 (2015).

  130. 130.

    Rudic, R. D. et al. Bioinformatic analysis of circadian gene oscillation in mouse aorta. Circulation 112, 2716–2724 (2005).

  131. 131.

    Nakazato, R. et al. The intrinsic microglial clock system regulates interleukin-6 expression. Glia 65, 198–208 (2017).

  132. 132.

    Alvarez-Sanchez, N. et al. Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance. Brain Behav. Immun. 50, 101–114 (2015).

  133. 133.

    Borniger, J. C. et al. Time-of-day dictates transcriptional inflammatory responses to cytotoxic chemotherapy. Sci. Rep 7, 41220 (2017).

  134. 134.

    Durrington, H. J., Farrow, S. N. & Ray, D. Recent advances in chronotherapy for the management of asthma. ChronoPhysiology Ther. 4, 125–135 (2014).

Download references

Acknowledgements

The authors thank V. Lavilla for creating the video and M. F. Loudon for providing the voice-over to it. C.S. is funded by the German Research Foundation (DFG) (Emmy-Noether grant (SCHE 1645/2-1) and SFB914 projects B09 and Z03), the European Research Council (ERC; starting grant 635872, CIRCODE), the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research). J.G. is an Arthritis Research UK Career Development Fellow (Ref. 20629). A.L. acknowledges the support of the Wellcome Trust (grant 107851/Z/15/Z).

Author information

Affiliations

  1. Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians–University Munich, Biomedical Centre, Planegg, Martinsried, Germany

    • Christoph Scheiermann
    •  & Louise Ince
  2. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

    • Christoph Scheiermann
  3. School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    • Julie Gibbs
    •  & Andrew Loudon

Authors

  1. Search for Christoph Scheiermann in:

  2. Search for Julie Gibbs in:

  3. Search for Louise Ince in:

  4. Search for Andrew Loudon in:

Contributions

All authors contributed to the research, discussion of content, writing and review of this manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Christoph Scheiermann or Andrew Loudon.

Supplementary information

  1. Movie 1: Rhythmic leukocyte activity throughout the body. Migration of leukocytes from blood to tissues (and back) is regulated at multiple levels by the circadian clock. In mice, blood leukocyte content is high during the day (rest phase) and lower at night (active phase). The factors, which generate these oscillations vary between cells and tissues. For example, neutrophils in the blood express higher levels of the chemokine receptor CXCR4 during the late day. This receptor drives neutrophil homing to bone marrow, which is therefore elevated at this time point. During the night, CXCR4 expression is reduced and less homing occurs to this organ. In the lung, resident stromal cells rhythmically produce the neutrophil chemoattractant CXCL5. Inflammatory challenge by lipopolysaccharide (LPS) inhalation during the day stimulates greater production of CXCL5 than challenge at night. The differential production of chemoattractant, along with greater numbers of neutrophils in blood, therefore leads to increased neutrophil influx to the lung during the day. By contrast, cells largely home to lymph nodes at night. During the day, T cell and B cell expression of the lymph node-homing receptor CCR7 is low, and few cells migrate into the lymph node. In addition, expression of S1PR1, the receptor which mediates lymphocyte egress, is high and cells are more prone to leave the lymph node during the day. At night, the inverse occurs and T cells and B cells are retained in the lymph node for longer. Differentiation of cells is also regulated by time-of-day, as in the case of TH17 cell development in the gut. During the day, levels of the differentiation factor RORγt are high and increased differentiation is observed relative to the dark phase. At night, RORγt activity is repressed by NFIL3 and so the differentiation stimulus is reduced. In this way, the body is primed to respond differently to inflammatory challenge at different times of day, and disruption to the circadian rhythm can have severe consequences for immune function

Glossary

Circadian

A free-running rhythm with a period of approximately 24 h that persists in the absence of external entrainment, such as in constant darkness.

Suprachiasmatic nuclei

(SCN). A bilateral structure in the anterior hypothalamus, home to the central pacemaker, which processes light input and conveys timing information to the rest of the body.

Diurnal

A pattern that occurs over the course of a day in which external entrainment (such as light–dark cycles) is used; the onset of the light cycle is defined as Zeitgeber time 0 (ZT0).

Period circadian protein homologue 1

(PER1). PER1, PER2 and PER3 are PAS (PER–ARNT–SIM) domain-containing proteins that associate with CRY proteins to inhibit BMAL1–CLOCK-mediated gene expression.

REV-ERB

REV-ERBα (encoded by NR1D1) and REV-ERBβ (encoded by NR1D2) are transcriptional repressors that bind to ROR response element (RORE) motifs in the BMAL1 promoter to regulate the rhythmic expression of BMAL1.

Cryptochromes

(CRYs). CRY1 and CRY2 are transcriptional repressors that associate with PER proteins to inhibit BMAL1–CLOCK-mediated gene transcription.

Brain and muscle ARNT-like 1

(BMAL1). A basic helix–loop–helix PER–ARNT–SIM (bHLH–PAS) domain transcription factor that dimerizes with CLOCK to bind E-boxes in gene promoters to induce circadian gene expression.

CLOCK

(Circadian locomoter output cycles kaput). A basic helix–loop–helix PER–ARNT–SIM (bHLH–PAS) domain transcription factor that can dimerize with BMAL1 to regulate circadian gene expression.

Zeitgeber time

Zeitgeber, literally ‘time giver’, is a cue (such as light) that entrains the circadian clock. Zeitgeber time (ZT) is the time after light onset; for example, lights on is ZT0 and lights off is ZT12 in a 12 h light-12 h dark cycle.

Circadian time

(CT). A measure of subjective time used when organisms are isolated from Zeitgebers (for example, constant darkness). CT0 represents the start of subjective day and CT12 represents the start of subjective night.

RORα

The nuclear receptors RORα, RORβ and RORγ are transcriptional activators that bind to ROR response element (RORE) sites in target gene promoters.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41577-018-0008-4

Further reading