The Circadian Clock Controls Toll-like Receptor 9-mediated Innate and Adaptive Immunity

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2012 Feb 21

PMID 22342842

Citations 215

Authors

Adam C Silver

Alvaro Arjona

Wendy E Walker

Erol Fikrig

Affiliations

Soon will be listed here.

Abstract

Circadian rhythms refer to biologic processes that oscillate with a period of ~24 hr. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of Toll-like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy.

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References

Leclerc G, Boockfor F . Pulses of prolactin promoter activity depend on a noncanonical E-box that can bind the circadian proteins CLOCK and BMAL1. Endocrinology. 2005; 146(6):2782-90. DOI: 10.1210/en.2005-0100. View

Balsalobre A, Damiola F, Schibler U . A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell. 1998; 93(6):929-37. DOI: 10.1016/s0092-8674(00)81199-x. View

Scheff J, Calvano S, Lowry S, Androulakis I . Modeling the influence of circadian rhythms on the acute inflammatory response. J Theor Biol. 2010; 264(3):1068-76. DOI: 10.1016/j.jtbi.2010.03.026. View

Arjona A, Sarkar D . Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J Immunol. 2005; 174(12):7618-24. DOI: 10.4049/jimmunol.174.12.7618. View

Petrovsky N . Towards a unified model of neuroendocrine-immune interaction. Immunol Cell Biol. 2001; 79(4):350-7. DOI: 10.1046/j.1440-1711.2001.01029.x. View

Medzhitov R, Janeway Jr C . Innate immune induction of the adaptive immune response. Cold Spring Harb Symp Quant Biol. 2001; 64:429-35. DOI: 10.1101/sqb.1999.64.429. View

Ueda H, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y . System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet. 2005; 37(2):187-92. DOI: 10.1038/ng1504. View

Petrovsky N, Harrison L . The chronobiology of human cytokine production. Int Rev Immunol. 1998; 16(5-6):635-49. DOI: 10.3109/08830189809043012. View

Roberts J . Light and immunomodulation. Ann N Y Acad Sci. 2001; 917:435-45. DOI: 10.1111/j.1749-6632.2000.tb05408.x. View

10.

Esquifino A, Selgas L, Arce A, Maggiore V, Cardinali D . Twenty-four-hour rhythms in immune responses in rat submaxillary lymph nodes and spleen: effect of cyclosporine. Brain Behav Immun. 1996; 10(2):92-102. DOI: 10.1006/brbi.1996.0010. View

11.

Githeko A, Adungo N, Karanja D, Hawley W, Vulule J, Seroney I . Some observations on the biting behavior of Anopheles gambiae s.s., Anopheles arabiensis, and Anopheles funestus and their implications for malaria control. Exp Parasitol. 1996; 82(3):306-15. DOI: 10.1006/expr.1996.0038. View

12.

Keller M, Mazuch J, Abraham U, Eom G, Herzog E, Volk H . A circadian clock in macrophages controls inflammatory immune responses. Proc Natl Acad Sci U S A. 2009; 106(50):21407-12. PMC: 2795539. DOI: 10.1073/pnas.0906361106. View

13.

Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo J, Sassone-Corsi P . Circadian clock control by SUMOylation of BMAL1. Science. 2005; 309(5739):1390-4. DOI: 10.1126/science.1110689. View

14.

Bovbjerg D . Circadian disruption and cancer: sleep and immune regulation. Brain Behav Immun. 2003; 17 Suppl 1:S48-50. DOI: 10.1016/s0889-1591(02)00066-1. View

15.

Schroder K, Lichtinger M, Irvine K, Brion K, Trieu A, Ross I . PU.1 and ICSBP control constitutive and IFN-gamma-regulated Tlr9 gene expression in mouse macrophages. J Leukoc Biol. 2007; 81(6):1577-90. DOI: 10.1189/jlb.0107036. View

16.

Plitas G, Burt B, Nguyen H, Bamboat Z, DeMatteo R . Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis. J Exp Med. 2008; 205(6):1277-83. PMC: 2413026. DOI: 10.1084/jem.20080162. View

17.

Arjona A, Sarkar D . The circadian gene mPer2 regulates the daily rhythm of IFN-gamma. J Interferon Cytokine Res. 2006; 26(9):645-9. DOI: 10.1089/jir.2006.26.645. View

18.

Holzheimer R, Curley P, Saporoschetz I, Doherty J, Mannick J, Rodrick M . Circadian rhythm of cytokine secretion following thermal injury in mice: implications for burn and trauma research. Shock. 2002; 17(6):527-9. DOI: 10.1097/00024382-200206000-00015. View

19.

Medzhitov R . Toll-like receptors and innate immunity. Nat Rev Immunol. 2002; 1(2):135-45. DOI: 10.1038/35100529. View

20.

Akira S, Takeda K, Kaisho T . Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001; 2(8):675-80. DOI: 10.1038/90609. View