Circadian Rhythm, Hypothalamo-Pituitary Adrenal Axis, and Immunity: Physiological and Pathological Examples

Abstract

All living organisms; from single-celled microorganisms to humans, they have to adapt to changing environmental conditions to maintain their survival processes. Circadian rhythm is one of the most important mechanism that associated with this adaptation processes. There are biological clocks in the body, which are related to the circadian rhythm and have a hierarchical organization. The master circadian clock is located in the suprachiasmatic nucleus (SCN) of hypothalamus. SCN maintain body rhythms in synchronous with the light-dark cycle in the external environment. There are also peripheral oscillators that work in coordination with SCN. Neurological, endocrinological, and immunological functions in the body are under the influence of circadian and seasonal rhythms. Melatonin and cortisol (corticosterone in animals) are among the most important hormones that show circadian rhythm in the body. The body adapts to daily and seasonal changes with biological rhythms regulated by biological clocks. It is well known that the immune system is affected by the external environment. Changes in endocrine system, hypothalaomo-pituitary adrenal (HPA) axis, and immune system are marked, especially depending on the seasonal changes. Therefore, the immune system has close relationship with the circadian rhythm. Understanding relationship between physiological regulation of the circadian rhythm, HPA axis and immune activity is important for to keep our body in healthy conditions and struggle with the diseases as well. In current review, the interaction and relationship of genes and proteins related to the circadian rhythm with HPA axis and immune system parameters are discussed with both physiological and pathological examples.

Keywords

• Circadian rhythm
• immune system
• hypothalamo-pituitary adrenal axis
• healthy conditions
• disease

Sirkadiyen Ritim, Hipotalamo-Hipofizer Akrenal Aks ve Bağışıklık: Fizyolojik ve Patolojik Örnekler

Öz

Tek hücreli mikroorganizmalardan insanlara kadar, canlılar değişen çevre koşullarına uyum sağlamak zorundadır. Sirkadiyen ritim bu adaptasyonla ilişkili en önemli mekanizmadır. Vücutta sirkadiyen ritimle ilişkili, hiyerarşik organizasyona sahip, biyolojik saatler bulunmaktadır. Master sirkadiyen saat, hipotalamusun suprakiyazmatik nükleusunda (SCN) yer almaktadır. SCN, vücut ritimlerini dış ortamdaki aydınlık-karanlık döngüsüyle senkronize halde tutar. Merkezi saat olan SCN ile koordineli çalışan, periferal osilatörler de mevcuttur. Vücutta nörolojik, endokrinolojik ve immünolojik fonksiyonlar sirkadiyen ve mevsimsel ritimlerin etkisi altındadır. Vücutta sirkadiyen ritim gösteren hormonların başında melatonin ve kortizol (hayvanlarda kortikosteron) gelmektedir. Vücut günlük ve mevsimsel değişikliklere biyolojik saatleri vasıtasıyla düzenlenen biyolojik ritimlerle uyum sağlamaktadır. Bağışıklık sisteminin dış çevreden etkilendiği iyi bilinmektedir. Özellikle mevsim değişikliklerine bağlı olarak endokrin sistemde, hipotalamo-hipofizer adrenal aksta ve immün sistemde değişiklikler kendini belli etmektedir. Bununla birlikte immün sistem sirkadiyen ritimle de sıkı ilişkiye sahiptir. Sirkadiyen ritmin fizyolojik regülasyonu ve immün aktivite arasındaki ilişkinin anlaşılması sağlıklı yaşam ve hastalıklarla mücadele bakımından önem arz etmektedir. Yazımızda sirkadiyen ritimle ilişkili gen ve proteinlerin immün sistem parametreleri ile etkileşimi ve ilişkisi güncel fizyolojik ve patolojik örneklerle ele alınmaktadır.

Anahtar Kelimeler

• Sirkadiyen ritim
• immun sistem
• hipotalamo-hipofizer adrenal aks
• sağlık
• hastalık

References

1. Halberg, F. Physiologic 24-hour periodicity; general and procedural considerations with reference to the adrenal cycle. Int. Z. Vitaminforsch. Beih. 1959;10:225–296 .
2. Harmer, S. L., Panda, S. & Kay, S. A. Molecular bases of circadian rhythms. Annu. Rev. Cell Dev. Biol. 2001;17: 215–253.
3. Jagannath, A., Taylor, L., Wakaf, Z., Vasudevan, S. R. & Foster, R. G. The genetics of circadian rhythms, sleep and health. Hum. Mol. Genet. 2017; 26: R128–R138.
4. Poggiogalle E, Jamshed H, Peterson CM. Circadian regulation of glucose, lipid, and energy metabolism in humans. Metabolism. 2018;84:11-27.
5. Chen, S.-K., Badea, T. C. & Hattar, S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature 2011;476:92–95.
6. Oike H, Oishi K, Kobori M. Nutrients, Clock Genes, and Chrononutrition. Curr Nutr Rep. 2014;3(3):204-212.
7. Fagiani F, Di Marino D, Romagnoli A, Travelli C, Voltan D, Mannelli LDC, Racchi M, Govoni S, Lanni C. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther. 2022;7(1):41.
8. Poole J, Kitchen GB. Circadian regulation of innate immunity in animals and humans and implications for human disease. Semin Immunopathol. 2022;44(2):183-192.

9. Bray, M. S.Young, M. E. Regulation of fatty acid metabolism by cell autonomous circadian clocks: time to fatten up on information? J Biol Chem, 2011;286: 11883-11889.
10. Bass, J., (2012). Circadian topology of metabolism. Nature, 491, 348-356.
11. Maury, E., Ramsey, K. M.Bass, J.. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ Res, 2010;106: 447-462.
12. Konturek, P. C., Brzozowski, T.Konturek, S. J.. Gut clock: implication of circadian rhythms in the gastrointestinal tract. J Physiol Pharmacol, 2011;62: 139-150.
13. Eastman C, Mistlberger R, Rechtschaffen A. Suprachiasmatic nuclei lesions eliminate circadian temperature and sleep rhythms in the rat. Physiol Behav 1984;32:357–368.
14. Reppert S, Perlow M, Ungerleider L, Mishkin M, Tamarkin L, Orloff D, Hoffman H, Klein D. Effects of damage to the suprachiasmatic area of the anterior hypothalamus on the Daily melatonin and cortisol rhythms in the rhesus monkey. J Neurosci 1981;1:1414.
15. Challet E. Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals. Endocrinology 2007;148:5648–5655.
16. Shigeyoshi Y, Taguchi K, Yamamoto S, Takekida S, Yan L, Tei H, Moriya T, Shibata S, Loros JJ, Dunlap JC, Okamura H. Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 1997;91:1043–1053.
17. Batra T, Malik I, Prabhat A, Bhardwaj SK, Kumar V. Sleep in unnatural times: illuminated night negatively affects sleep and associated hypothalamic gene expressions in diurnal zebra finches. Proc R Soc B Biol Sci 2020;287:20192952.
18. Mishra I, Knerr RM, Stewart AA, Payette WI, Richter MM, Ashley NT. Light at night disrupts diel patterns of cytokine gene expression and endocrine profiles in zebra finch (Taeniopygia guttata). Sci Rep 2019;9:15833.
19. Ren D, Zhang J, Yang L, Wang X, Wang Z, Huang D, Tian C, Hu B. Circadian genes period1b and period2 differentially regulate inflammatory responses in zebrafish. Fish Shellfish Immunol 2018; 77:139–146.
20. Lang V, Ferencik S, Ananthasubramaniam B, Kramer A, Maier B. Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice. Elife 2021;10:e62469.
21. Lewis AJ, Zhang X, Griepentrog JE, Yuan D, Collage RD, Waltz PK, Angus DC, Zuckerbraun BS, Rosengart MR. Blue light enhances bacterial clearance and reduces organ injury during sepsis. Crit Care Med 2018;46:e779–e787.
22. Leibetseder V, Humpeler S, Svoboda M, Schmid D, Thalhammer T, Zuckermann A, Marktl W, Ekmekcioglu C. Clock genes display rhythmic expression in human hearts. Chronobiol Int 2009;26:621–636.
23. Elmadjian F, Pincus G. A study of the diurnal variations in circulating lymphocytes in normal and psychotic subjects. J Clin Endocrinol Metab. 1946;6:287–294.
24. Halberg F, Johnson EA, Brown BW, Bittner JJ. Susceptibility rhythm to E. coli endotoxin and bioassay. Proc Soc Exp Biol Med. 1960;103:142–144.
25. Keller M, et al. A circadian clock in macrophages controls inflammatory immune responses. Proc Natl Acad Sci U S A. 2009;106(50):21407–21412.
26. Pariollaud M, et al. Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. J Clin Invest. 2018;128(6):2281–2296.
27. Curtis AM, et al. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc Natl Acad Sci U S A. 2015;112(23):7231–7236.
28. Edgar RS, et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proc Natl Acad Sci U S A. 2016;113(36):10085–10090.
29. Haspel JA, Anafi R, Brown MK, Cermakian N, Depner C, Desplats P, Gelman AE, Haack M, Jelic S, Kim BS, Laposky AD, Lee YC, Mongodin E, Prather AA, Prendergast BJ, Reardon C, Shaw AC, Sengupta S, Szentirmai É, Thakkar M, Walker WE, Solt LA. Perfect timing: circadian rhythms, sleep, and immunity- an NIH workshop summary. JCI Insight. 2020;5(1):e131487.
30. Zhao Y, et al. Uncoverin g the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice. Blood. 2017;130(18):1995–2005.
31. Wu X, Tian J, Wang S. Insight into non-pathogenic Th17 cells in autoimmune diseases. Front Immunol. 2018;9:1112.
32. Melo-Gonzalez F, Hepworth MR. Functional and phenotypic heterogeneity of group 3 innate lymphoid cells. Immunology. 2017;150(3):265–275.35.
33. Yang XO, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28(1):29–39.
34. Amir M, et al. REV-ERBα regulates TH17 cell development and autoimmunity. Cell Rep. 2018;25(13):3733–3749.e8.
35. Farez MF, et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell. 2015;162(6):1338–1352.
36. Adrover JM, et al. A neutrophil timer coordinates immune defense and vascular protection. Immunity. 2019;50(2):390–402.e10.
37. Haus E, Smolensky MH. Biologic rhythms in the immune system. Chronobiol Int. 1999; 16:581–622.
38. Kalsbeek, A., van der Spek, R., Lei, J., Endert, E., Buijs, R. M., Fliers, E. 2012. "Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis". Molecular and Cellular Endocrinology, 349(1), 20–29.
39. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci, 2009;10(6):397–409.
40. Stephens, M. A. C., Wand, G. "Stress and the HPA axis: Role of glucocorticoids in alcohol dependence". Alcohol Research: Current Reviews, 2012;34(4), 468–483.
41. Van Bodegom M, Homberg JR, Henckens MJAG. Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure. Front Cell Neurosci. 2017;11:87.
42. Dumbell R, Matveeva O, Oster H. Circadian Clocks, Stress, and Immunity. Front Endocrinol (Lausanne). 2016;7:37.
43. Lightman SL, Conway-Campbell BL. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci 2010;11(10):710–8.
44. Dickmeis T, Weger BD, Weger M. The circadian clock and glucocorticoids – interactions across many time scales. Mol Cell Endocrinol 2013;380(1–2):2–15.
45. Walker JJ, Spiga F, Waite E, Zhao Z, Kershaw Y, Terry JR, et al. The origin of glucocorticoid hormone oscillations. PLoS Biol 2012;10(6):e1001341.
46. Walker JJ, Spiga F, Gupta R, Zhao Z, Lightman SL, Terry JR. Rapid intra-adrenal feedback regulation of glucocorticoid synthesis. J R Soc Interface 2015;12(102):20140875.
47. Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986;233(4764):652–4.
48. Van der Meer MJ, Sweep CG, Rijnkels CE, Pesman GJ, Tilders FJ, Kloppenborg PW, et al. Acute stimulation of the hypothalamic-pituitary-adrenal axis by IL-1 beta, TNF alpha and IL-6: a döşe response study. J Endocrinol Invest 1996;19(3):175–82.
49. Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999;79(1):1–71.
50. Saphier D. Neuroendocrine effects of interferon-alpha in the rat. Adv Exp Med Biol 1995; 373:209–18.
51. Kovacs KJ, Elenkov IJ. Differential dependence of ACTH secretion induced by various cytokines on the integrity of the paraventricular nucleus. J Neuroendocrinol 1995;7(1):15–23.
52. Harbuz MS, Stephanou A, Sarlis N, Lightman SL. The effects of recombinant human interleukin (IL)-1 alpha, IL-1 beta or IL-6 on hypothalamo-pituitary-adrenal axis activation. J Endocrinol 1992; 133(3):349–55.
53. Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function*. Annu Rev Immunol 2000; 18:309–45.
54. Caramori G, Adcock I. Anti-inflammatory mechanisms of glucocorticoids targeting granulocytes. Curr Drug Targets Inflamm Allergy 2005; 4(4): 455–63.
55. Vandevyver S, Dejager L, Tuckermann J, Libert C. New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 2013;154(3):993–1007.
56. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids – new mechanisms for old drugs. N Engl J Med 2005; 353(16):1711–23.
57. De Bosscher K, Vanden Berghe W, Haegeman G. Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 2006;25(51):6868–86.
58. D’Adamio F, Zollo O, Moraca R, Ayroldi E, Bruscoli S, Bartoli A, et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity 1997; 7(6):803–12.
59. Lasa M, Abraham SM, Boucheron C, Saklatvala J, Clark AR. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol 2002;22(22):7802–11.
60. Perretti M, D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 2009;9(1):62–70.
61. Xu D, Makkinje A, Kyriakis JM. Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem 2005;280(4):2924–33.
62. Park SK, Beaven MA. Mechanism of upregulation of the inhibitory regulator, src-like adaptor protein (SLAP), by glucocorticoids in mast cells. Mol Immunol 2009;46(3):492–7.
63. Dhabhar FS. Stress-induced augmentation of immune function – the role of stress hormones, leukocyte trafficking, and cytokines. Brain Behav Immun 2002;16(6):785–98.
64. Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 2015; 22(1–2):20–32.
65. Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 2009; 16(5):300–17.
66. Haus E, Lakatua DJ, Swoyer J, Sackett-Lundeen L. Chronobiology in hematology and immunology. Am J Anat. 1983; 168:467–517.
67. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008; 452:442–7.
68. Cutolo M. Chronobiology and the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2012; 24:312–8.
69. Hashiramoto A, Yamane T, Tsumiyama K, Yoshida K, Komai K, Yamada H et al. Mammalian clock gene Cryptochrome regulates arthritis via proinflammatory cytokine TNF-a. J Immunol 2010; 184:1560–65.
70. Gupta A, Shetty H. Circadian variation in stroke - a prospective hospital-based study. Int J Clin Pract. 2005; 59:1272–5.
71. Muller JE, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985; 313:1315–22.
72. Marfella R, et al. Morning blood pressure surge as a destabilizing factor of atherosclerotic plaque: role of ubiquitin-proteasome activity. Hypertension. 2007; 49:784–91.
73. Beker MC, Caglayan B, Yalcin E, Caglayan AB, Turkseven S, Gurel B, Kelestemur T, Sertel E, Sahin Z, Kutlu S, Kilic U, Baykal AT, Kilic E. Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT. Mol Neurobiol. 2018;55(3):2565-2576.
74. Shichita T, et al. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med. 2012; 18:911–7.
75. Suarez-Barrientos A, et al. Circadian variations of infarct size in acute myocardial infarction. Heart. 2011; 97:970–6.
76. Litinski M, Scheer FA, Shea SA. Influence of the circadian system on disease severity. Sleep Med Clin 2009; 4:143–63.
77. Zaslona Z, Case S, Early JO, Lalor SJ, McLoughlin RM, Curtis AM et al. The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma. Am J Physiol Lung Cell Mol Physiol 2017; 312: L855–60.
78. Harding K, Tilling K, MacIver C, Willis M, Joseph F, Ingram G et al. Seasonal variation in multiple sclerosis relapse. J Neurol 2017; 264:1059–67.
79. Downton P, Early JO, Gibbs JE. Circadian rhythms in adaptive immunity. Immunology. 2020 Dec;161(4):268-277.
80. Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol 2019; 26:27–40.
81. Born J, Lange T, Hansen K, M€olle M, Fehm HL. Effects of sleep and circadian rhythm on human circulating immune cells. J Immunol 1997; 158:4454–64.
82. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KHG. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 2010; 162:1–11.
83. Durrington HJ, Gioan-Tavernier GO, Maidstone RJ, Krakowiak K, Loudon ASI, Blaikley JF et al. Time of day affects eosinophil biomarkers in asthma: implications for diagnosis and treatment. Am J Respir Crit Care Med 2018; 198:1578–81.
84. Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol. 2013 Mar;13(3):190-8.
85. Smolensky MH, Lemmer B, Reinberg AE. Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma. Adv Drug Deliv Rev. 2007; 59:852–82.
86. Panzer SE, Dodge AM, Kelly EA, Jarjour NN. Circadian variation of sputum inflammatory cells in mild asthma. J Allergy Clin Immunol. 2003; 111:308–12.
87. Auvil-Novak SE, Novak RD, el Sanadi N. Twenty-four-hour pattern in emergency department presentation for sickle cell vaso-occlusive pain crisis. Chronobiol Int. 1996; 13:449–56.