Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-29T14:57:40.802Z Has data issue: false hasContentIssue false
  • English
  • Français

Glucocorticoid receptor signaling in leukocytes after early life adversity

Published online by Cambridge University Press:  13 August 2019

Martha M. C. Elwenspoek ,
Xenia Hengesch ,
Fleur A. D. Leenen ,
Krystel Sias ,
Sara Beatriz Fernandes ,
Violetta K. Schaan ,
Sophie B. Mériaux ,
Stephanie Schmitz ,
Fanny Bonnemberger  and
Hartmut Schächinger
...Show all authors
Martha M. C. Elwenspoek
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg Department of Immunology, Research Institute of Psychobiology, University of Trier, D-54290Trier, Germany
Xenia Hengesch
Affiliation:
Department of Clinical Psychophysiology, Institute of Psychobiology, University of Trier, Germany
Fleur A. D. Leenen
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg Department of Immunology, Research Institute of Psychobiology, University of Trier, D-54290Trier, Germany
Krystel Sias
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg
Sara Beatriz Fernandes
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg
Violetta K. Schaan
Affiliation:
Institute for Health and Behaviour, Research Unit INSIDE, University of Luxembourg, Grand-Duchy of Luxembourg
Sophie B. Mériaux
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg
Stephanie Schmitz
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg
Fanny Bonnemberger
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg
Hartmut Schächinger
Affiliation:
Department of Clinical Psychophysiology, Institute of Psychobiology, University of Trier, Germany
Claus Vögele
Affiliation:
Institute for Health and Behaviour, Research Unit INSIDE, University of Luxembourg, Grand-Duchy of Luxembourg
Claude P. Muller
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg Department of Immunology, Research Institute of Psychobiology, University of Trier, D-54290Trier, Germany
Jonathan D. Turner*
Affiliation:
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, L-4354, Grand-Duchy of Luxembourg
*
Author for Correspondence: Jonathan D. Turner, Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354Esch-sur-Alzette, Grand-Duchy of Luxembourg. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).

Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.

Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

Keywords

DNA methylationearly life adversityFKBP5GILZglucocorticoid receptorNR3C1
Type
Regular Articles
Information
Development and Psychopathology , Volume 32 , Issue 3 , August 2020 , pp. 853 - 863
Check for updates
Copyright
Copyright © Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

#

Both authors contributed equally as senior authors.

References

Alexander, N., Kirschbaum, C., Wankerl, M., Stauch, B. J., Stalder, T., Steudte-Schmiedgen, S., … Miller, R. (2018). Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity. Psychoneuroendocrinology, 90, 68–75. doi:10.1016/j.psyneuen.2018.01.020CrossRefGoogle ScholarPubMed
Barker, D. J., & Osmond, C. (1986). Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet, 1, 1077–1081.CrossRefGoogle ScholarPubMed
Barton, A. S., Zakreski, E., & Pruessner, J. (2016). The effects of early life adversity on responses to the Montreal Imaging Stress Task. Psychoneuroendocrinology, 71, 67. doi:10.1016/j.psyneuen.2016.07.175CrossRefGoogle Scholar
Batten, S. V., Aslan, M., Maciejewski, P. K., & Mazure, C. M. (2004). Childhood maltreatment as a risk factor for adult cardiovascular disease and depression. Journal of Clinical Psychiatry, 65, 249–254.CrossRefGoogle ScholarPubMed
Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C. M., & Mondelli, V. (2016). Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Molecular Psychiatry, 21, 642–649. doi:10.1038/mp.2015.67CrossRefGoogle ScholarPubMed
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, 57, 289–300.Google Scholar
Cain, D. W., & Cidlowski, J. A. (2017). Immune regulation by glucocorticoids. Nature Reviews Immunology, 17, 233–247. doi:10.1038/nri.2017.1CrossRefGoogle ScholarPubMed
Cao-Lei, L., Leija, S. C., Kumsta, R., Wust, S., Meyer, J., Turner, J. D., & Muller, C. P. (2011). Transcriptional control of the human glucocorticoid receptor: Identification and analysis of alternative promoter regions. Human Genetics, 129, 533–543. doi:10.1007/s00439-011-0949-1CrossRefGoogle ScholarPubMed
Cao-Lei, L., Suwansirikul, S., Jutavijittum, P., Meriaux, S. B., Turner, J. D., & Muller, C. P. (2013). Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain. Journal of Psychiatric Research, 47, 1597–1607. doi:10.1016/j.jpsychires.2013.07.022CrossRefGoogle ScholarPubMed
Chiang, J.J., Bower, J.E., Irwin, M.R., Taylor, S.E., Fuligni, A.J. (2017) Adiposity moderates links from early adversity and depressive symptoms to inflammatory reactivity to acute stress during late adolescence. Brain Behavior and Immunity, 6, 146–155. doi:10.1016/j.bbi.2017.06.015. Epub 2017 Jun 28.CrossRefGoogle Scholar
Cole, S.W. (2014). Human social genomics. PLoS Genetics, 10, e1004601.CrossRefGoogle ScholarPubMed
Drury, S.S., Theall, K., Gleason, M.M., Smyke, A.T., De Vivo, I., Wong, J.Y., … Nelson, C.A. (2012). Telomere length and early severe social deprivation: Linking early adversity and cellular aging. Molecular Psychiatry, 17, 719–727.CrossRefGoogle ScholarPubMed
Elwenspoek, M. M. C., Hengesch, X., Leenen, F. A. D., Schritz, A., Sias, K., Schaan, V. K., … Muller, C. P. (2017). Proinflammatory T Cell Status Associated with Early Life Adversity. Journal of Immunology, 199, 4046–4055. doi:10.4049/jimmunol.1701082CrossRefGoogle ScholarPubMed
Elwenspoek, M. M. C., Kuehn, A., Muller, C. P., & Turner, J. D. (2017). The effects of early life adversity on the immune system. Psychoneuroendocrinology, 82, 140–154. doi:10.1016/j.psyneuen.2017.05.012CrossRefGoogle ScholarPubMed
Elwenspoek, M. M. C., Sias, K., Hengesch, X., Schaan, V. K., Leenen, F. A. D., Adams, P., … Turner, J. D. (2017). T Cell Immunosenescence after Early Life Adversity: Association with Cytomegalovirus Infection. Frontiers in Immunology, 8, 1263. doi:10.3389/fimmu.2017.01263CrossRefGoogle ScholarPubMed
Hengesch, X., Elwenspoek, M. M. C., Schaan, V. K., Larra, M. F., Finke, J. B., Zhang, X., … Schachinger, H. (2018). Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity. Child Abuse & Neglect, 85, 137–144. doi:10.1016/j.chiabu.2018.04.002CrossRefGoogle ScholarPubMed
Hodel, A.S., Hunt, R.H., Cowell, R.A., Van Den Heuvel, S.E., Gunnar, M.R., Thomas, K.M., (2015). Duration of early adversity and structural brain development in post-institutionalized adolescents. Neurolimage, 105, 112–119.CrossRefGoogle ScholarPubMed
Hogg, K., Blair, J. D., McFadden, D. E., von Dadelszen, P., & Robinson, W. P. (2013). Early onset pre-eclampsia is associated with altered DNA methylation of cortisol-signalling and steroidogenic genes in the placenta. PLoS One, 8, e62969. doi:10.1371/journal.pone.0062969CrossRefGoogle ScholarPubMed
Julian, M. M. (2013). Age at adoption from institutional care as a window into the lasting effects of early experiences. Clinical Child and Family Psychology Review, 16, 101–145. doi:10.1007/s10567-013-0130-6CrossRefGoogle Scholar
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., … Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience, 16, 33–41. doi:10.1038/nn.3275CrossRefGoogle ScholarPubMed
Klinitzke, G., Romppel, M., Hauser, W., Brahler, E., Glaesmer, H. (2012). The German Version of the Childhood Trauma Questionnaire (CTQ): Psychometric characteristics in a representative sample of the general population. Psychotherapie, Psychosomatik, medizinische Psychologie [Psychotherapy, Psychosomatics and Neuropsychiatry], 62, 47–51.Google Scholar
Knight, C. H., & Sorensen, A. (2001). Windows in early mammary development: Critical or not? Reproduction, 122, 337–345. doi:10.1530/rep.0.1220337CrossRefGoogle ScholarPubMed
Koss, K. J., & Gunnar, M. R. (2018). Annual Research Review: Early adversity, the hypothalamic-pituitary-adrenocortical axis, and child psychopathology. Journal of Child Psychology and Psychiatry, 59, 327–346. doi:10.1111/jcpp.12784CrossRefGoogle ScholarPubMed
Labonte, B., Azoulay, N., Yerko, V., Turecki, G., & Brunet, A. (2014). Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Translational Psychiatry, 4, e368. doi:10.1038/tp.2014.3CrossRefGoogle ScholarPubMed
Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., & Turecki, G. (2012). Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biological Psychiatry, 72, 41–48. doi:10.1016/j.biopsych.2012.01.034CrossRefGoogle Scholar
Leenen, F. A., Muller, C. P., & Turner, J. D. (2016). DNA methylation: Conducting the orchestra from exposure to phenotype? Clinical Epigenetics, 8, 92. doi:10.1186/s13148-016-0256-8CrossRefGoogle Scholar
Li-Tempel, T., Larra, M. F., Sandt, E., Meriaux, S. B., Schote, A. B., Schachinger, H., … Turner, J. D. (2016). The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation. Clin Epigenetics, 8, 12. doi:10.1186/s13148-016-0180-yCrossRefGoogle ScholarPubMed
Louis, G. B., Damstra, T., Díaz-Barriga, F., Faustman, E., Hass, U., Kavlock, R., … Sheldon, L. (2006). Principles for evaluating health risks in children associated with exposure to chemicals. Environmental Health Criteria, 237, 1–327.Google Scholar
Martin-Blanco, A., Ferrer, M., Soler, J., Salazar, J., Vega, D., Andion, O., … Pascual, J. C. (2014). Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder. Journal of Psychiatric Research, 57, 34–40. doi:10.1016/j.jpsychires.2014.06.011CrossRefGoogle ScholarPubMed
McCauley, J., Kern, D. E., Kolodner, K., Dill, L., Schroeder, A. F., DeChant, H. K., … Bass, E.B. (1997). Clinical characteristics of women with a history of childhood abuse: Unhealed wounds. JAMA, 277, 1362–1368.CrossRefGoogle ScholarPubMed
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., … Meaney, M. J. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342–348. doi:10.1038/nn.2270CrossRefGoogle ScholarPubMed
Melas, P. A., Wei, Y., Wong, C. C., Sjoholm, L. K., Aberg, E., Mill, J., … Lavebratt, C. (2013). Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. The International Journal of Neuropsychopharmacology, 16, 1513–1528. doi:10.1017/S1461145713000102CrossRefGoogle ScholarPubMed
Miller, G. E., Chen, E, Shalowitz, M. U., Story, R. E., Leigh, A. K. K., Ham, P., & Cole, S. W. (2018). Divergent transcriptional profiles in pediatric asthma patients of low and high socioeconomic status. Pediatric Pulmonology, 53, 710–719.CrossRefGoogle ScholarPubMed
Oakley, R. H., & Cidlowski, J. A. (2013). The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease. The Journal of Allergy and Clinical Immunology, 132, 1033–1044. doi:10.1016/j.jaci.2013.09.007CrossRefGoogle ScholarPubMed
Pace, T. W., Wingenfeld, K., Schmidt, I., Meinlschmidt, G., Hellhammer, D. H., & Heim, C. M. (2012). Increased peripheral NF-kappaB pathway activity in women with childhood abuse-related posttraumatic stress disorder. Brain, Behavior, and Immunity, 26, 13–17. doi:10.1016/j.bbi.2011.07.232CrossRefGoogle ScholarPubMed
Palma-Gudiel, H., Cordova-Palomera, A., Leza, J. C., & Fananas, L. (2015). Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neuroscience & Biobehavioral Reviews, 55, 520–535. doi:10.1016/j.neubiorev.2015.05.016CrossRefGoogle ScholarPubMed
Perroud, N., Paoloni-Giacobino, A., Prada, P., Olie, E., Salzmann, A., Nicastro, R., … Malafosse, A. (2011). Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma. Translational Psychiatry, 1, e59. doi:10.1038/tp.2011.60CrossRefGoogle ScholarPubMed
Perroud, N., Rutembesa, E., Paoloni-Giacobino, A., Mutabaruka, J., Mutesa, L., Stenz, L., … Karege, F. (2014). The Tutsi genocide and transgenerational transmission of maternal stress: Epigenetics and biology of the HPA axis. World Journal of Biological Psychiatry, 15, 334–345. doi:10.3109/15622975.2013.866693CrossRefGoogle ScholarPubMed
Phillips, S. P., & Carver, L. (2015). Early parental loss and self-rated health of older women and men: A population-based, multi-country study. PLoS One, 10, e0120762. doi:10.1371/journal.pone.0120762CrossRefGoogle ScholarPubMed
R Core Team. (2016). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.Google Scholar
Reid, B.M., Coe, C.L., Doyle, C.M., Sheerar, D., Slukvina, A., Donzella, B., Gunnar, M.R. (2019) Persistent Skewing of the T-Cell Profile in Adolescents Adopted Internationally from Institutional Care. Brain, Behavior, and Immunity, 77, 168–177.CrossRefGoogle ScholarPubMed
Rentscher, K. E., Carroll, J.E., Repetti, R. L., Cole, S. W., Reynolds, B.M., & Robles, T.F. (2019). Chronic stress exposure and daily stress appraisals relate to biological aging marker p16(INK4a). Psychoneuroendocrinology, 102, 139–148.CrossRefGoogle Scholar
Rice, D., & Barone, S. Jr. (2000). Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental Health Perspectives, 108, 511–533. doi:10.1289/ehp.00108s3511Google ScholarPubMed
Romens, S. E., McDonald, J., Svaren, J., & Pollak, S. D. (2015). Associations between early life stress and gene methylation in children. Child Development, 86, 303–309. doi:10.1111/cdev.12270CrossRefGoogle ScholarPubMed
Ronchetti, S., Migliorati, G., & Riccardi, C. (2015). GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids. Frontiers in Endocrinology (Lausanne), 6, 170. doi:10.3389/fendo.2015.00170Google ScholarPubMed
Schote, A. B., Turner, J. D., Schiltz, J., & Muller, C. P. (2007). Nuclear receptors in human immune cells: Expression and correlations. Molecular Immunology, 44, 1436–1445. doi:10.1016/j.molimm.2006.04.021CrossRefGoogle ScholarPubMed
Schroeder, H. (2011). Developmental brain and behaviour toxicity of air pollutants. A focus on the effects of Polycyclic Aromatic hydrocarbons (PAHs). Critical Reviews in Environmental Science and Technology, 41, 2026–2047.CrossRefGoogle Scholar
Slobedman, B., Stern, J.L., Cunningham, A.L., Abendroth, A., Abate, D.A., Mocarski, E.S. (2004) Impact of human cytomegalovirus latent infection on myeloid progenitor cell gene expression. Journal of Virology, 78, 4054–62.CrossRefGoogle ScholarPubMed
Steiger, H., Labonte, B., Groleau, P., Turecki, G., & Israel, M. (2013). Methylation of the glucocorticoid receptor gene promoter in bulimic women: Associations with borderline personality disorder, suicidality, and exposure to childhood abuse. International Journal of Eating Disorders, 46, 246–255. doi:10.1002/eat.22113CrossRefGoogle ScholarPubMed
Turecki, G., & Meaney, M. J. (2016). Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review. Biological Psychiatry, 79, 87–96. doi:10.1016/j.biopsych.2014.11.022CrossRefGoogle ScholarPubMed
Turner, J. D. (2018). Childhood adversity from conception onwards: Are our tools unnecessarily hindering us? Journal of Behavioral Medicine, 41, 568–570. doi:10.1007/s10865-018-9939-2CrossRefGoogle ScholarPubMed
Turner, J. D. (2018). Holistic, personalized, immunology? The effects of socioeconomic status on the transcriptional milieu of immune cells. Pediatric Pulmonology, 53, 696–697CrossRefGoogle ScholarPubMed
Turner, J. D., & Muller, C. P. (2005). Structure of the glucocorticoid receptor (NR3C1) gene 5' untranslated region: Identification, and tissue distribution of multiple new human exon 1. J Molecular Endocrinology, 35, 283–292. doi:10.1677/jme.1.01822CrossRefGoogle ScholarPubMed
Tyrka, A. R., Parade, S. H., Welch, E. S., Ridout, K. K., Price, L. H., Marsit, C., … Carpenter, L. L. (2016). Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: Associations with early adversity and depressive, anxiety and substance-use disorders. Translational Psychiatry, 6, e848. doi:10.1038/tp.2016.112CrossRefGoogle ScholarPubMed
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults. PLoS One, 7, e30148. doi:10.1371/journal.pone.0030148CrossRefGoogle ScholarPubMed
van der Knaap, L. J., Riese, H., Hudziak, J. J., Verbiest, M. M., Verhulst, F. C., Oldehinkel, A. J., & van Oort, F. V. (2014). Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Translational Psychiatry, 4, e381. doi:10.1038/tp.2014.22CrossRefGoogle ScholarPubMed
van Ijzendoorn., M. H., Palacios, J., Sonuga-Barke, E. J., Gunnar, M. R., Vorria, P., McCall, R. B., … Juffer, F. (2011). Children in institutional care: Delayed development and resilience. Monographs of the Society for Research in Child Development, 76, 8–30. doi:10.1111/j.1540-5834.2011.00626.xCrossRefGoogle ScholarPubMed
Vukojevic, V., Kolassa, I. T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., … de Quervain, D. J. (2014). Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. Journal of Neuroscience, 34, 10274–10284. doi:10.1523/JNEUROSCI.1526-14.2014CrossRefGoogle ScholarPubMed
Wang, S., Dou, Y., Yang, H., Ni, A., Zhang, R., Qian, J. (2017) Alteration of glucocorticoid receptors and exacerbation of inflammation during lytic cytomegalovirus infection in THP-1 cells. FEBS Open Bio, 7, 1924–1931. doi:10.1002/2211-5463.12334CrossRefGoogle ScholarPubMed
Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., … Meaney, M. J. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847–854. doi:10.1038/nn1276CrossRefGoogle ScholarPubMed
Witzmann, S. R., Turner, J. D., Meriaux, S. B., Meijer, O. C., & Muller, C. P. (2012). Epigenetic regulation of the glucocorticoid receptor promoter 1(7) in adult rats. Epigenetics, 7, 1290–1301. doi:10.4161/epi.22363CrossRefGoogle Scholar
Supplementary material: PDF

Elwenspoek et al. supplementary material

Elwenspoek et al. supplementary material
Download Elwenspoek et al. supplementary material(PDF)
PDF 106.9 KB