Decreased mononuclear cell NR3C1 SKA2 and FKPB5 expression levels among adult survivors of suicide bombing terror attacks in childhood are associated with the development of PTSD.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
16 Oct 2023
16 Oct 2023
Historique:
received:
05
03
2023
accepted:
19
09
2023
revised:
01
09
2023
medline:
17
10
2023
pubmed:
17
10
2023
entrez:
16
10
2023
Statut:
aheadofprint
Résumé
Life threatening trauma and the development of PTSD during childhood, may each associate with transcriptional perturbation of immune cell glucocorticoid reactivity, yet their separable longer term contributions are less clear. The current study compared resting mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, its trans-activator spindle and kinetochore-associated protein 2 (SKA2), and its co-chaperon FKBP prolyl isomerase 5 (FKBP5), between a cohort of young adults first seen at the Hadassah Emergency Department (ED) after surviving a suicide bombing terror attack during childhood, and followed longitudinally over the years, and matched healthy controls not exposed to life threatening trauma. While significant reductions in mononuclear cell gene expression levels were observed among young adults for all three transcripts following early trauma exposure, the development of subsequent PTSD beyond trauma exposure, accounted for a small but significant portion of the variance in each of the three transcripts. Long-term perturbation in the expression of immune cell glucocorticoid response transcripts persists among young adults who develop PTSD following life threatening trauma exposure in childhood, denoting chronic dysregulation of immune stress reactivity.
Identifiants
pubmed: 37845495
doi: 10.1038/s41380-023-02278-7
pii: 10.1038/s41380-023-02278-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
Références
van Bodegom M, Homberg JR, Henckens M. Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure. Front Cell Neurosci. 2017;11:87.
pubmed: 28469557
pmcid: 5395581
Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29–39.
pubmed: 21888923
doi: 10.1016/j.physbeh.2011.08.019
Cattane N, Vernon AC, Borsini A, Scassellati C, Endres D, Capuron L, et al. European College of Neuropsychopharmacology ImmunoNeuroPsychiatry Thematic Working G. Preclinical animal models of mental illnesses to translate findings from the bench to the bedside: Molecular brain mechanisms and peripheral biomarkers associated to early life stress or immune challenges. Eur Neuropsychopharmacol. 2022;58:55–79.
pubmed: 35235897
doi: 10.1016/j.euroneuro.2022.02.002
Wieck A, Grassi-Oliveira R, Hartmann do Prado C, Teixeira AL, Bauer ME. Neuroimmunoendocrine interactions in post-traumatic stress disorder: focus on long-term implications of childhood maltreatment. Neuroimmunomodulation. 2014;21:145–51.
pubmed: 24557048
doi: 10.1159/000356552
Tursich M, Neufeld RW, Frewen PA, Harricharan S, Kibler JL, Rhind SG, et al. Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis. Transl Psychiatry. 2014;4:e413.
pubmed: 25050993
pmcid: 4119223
doi: 10.1038/tp.2014.56
Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Mol Psychiatry. 2016;21:642–9.
pubmed: 26033244
doi: 10.1038/mp.2015.67
Lin JE, Neylan TC, Epel E, O’Donovan A. Associations of childhood adversity and adulthood trauma with C-reactive protein: a cross-sectional population-based study. Brain Behav Immun. 2016;53:105–12.
pubmed: 26616398
doi: 10.1016/j.bbi.2015.11.015
Peruzzolo TL, Pinto JV, Roza TH, Shintani AO, Anzolin AP, Gnielka V, et al. Inflammatory and oxidative stress markers in post-traumatic stress disorder: a systematic review and meta-analysis. Mol Psychiatry. 2022;27:3150–63.
pubmed: 35477973
doi: 10.1038/s41380-022-01564-0
O’Donnell CJ, Schwartz Longacre L, Cohen BE, Fayad ZA, Gillespie CF, et al. Posttraumatic stress disorder and cardiovascular disease: state of the science, knowledge gaps, and research opportunities. JAMA Cardiol. 2021;6:1207–16.
pubmed: 34259831
doi: 10.1001/jamacardio.2021.2530
Pace TW, Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011;25:6–13.
pubmed: 20934505
doi: 10.1016/j.bbi.2010.10.003
Shalev A, Benarroch F, Goltser-Dubner T, Canetti L, Saloner C, Roichman A, et al. Long-term immune alterations accompanying chronic posttraumatic stress disorder following exposure to suicide bomb terror incidents during childhood. Neuropsychobiology. 2017;76:130–5.
pubmed: 29949798
doi: 10.1159/000487275
Segman RH, Goltser-Dubner T, Weiner I, Canetti L, Galili-Weisstub E, Milwidsky A, et al. Blood mononuclear cell gene expression signature of postpartum depression. Mol Psychiatry. 2010;15:93–100.
pubmed: 19581911
doi: 10.1038/mp.2009.65
Kalla C, Goltser-Dubner T, Pevzner D, Canetti L, Mirman A, Ben-Yehuda A, et al. Resting mononuclear cell NR3C1 and SKA2 expression levels predict blunted cortisol reactivity to combat training stress among elite army cadets exposed to childhood adversity. Mol Psychiatry. 2021;26:6680–7.
pubmed: 33981010
doi: 10.1038/s41380-021-01107-z
Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71:423–31.
pubmed: 24576974
pmcid: 4032578
doi: 10.1001/jamapsychiatry.2013.4374
van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Amarouchi K, et al. Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: a prospective study. Biol Psychiatry. 2012;71:309–16.
pubmed: 22137507
doi: 10.1016/j.biopsych.2011.10.026
Palma-Gudiel H, Cordova-Palomera A, Leza JC, Fananas L. Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: a critical review. Neurosci Biobehav Rev. 2015;55:520–35.
pubmed: 26073068
doi: 10.1016/j.neubiorev.2015.05.016
Romens SE, McDonald J, Svaren J, Pollak SD. Associations between early life stress and gene methylation in children. Child Dev. 2015;86:303–9.
pubmed: 25056599
doi: 10.1111/cdev.12270
Gola H, Engler A, Morath J, Adenauer H, Elbert T, Kolassa IT, et al. Reduced peripheral expression of the glucocorticoid receptor alpha isoform in individuals with posttraumatic stress disorder: a cumulative effect of trauma burden. PLoS One. 2014;9:e86333.
pubmed: 24466032
pmcid: 3897679
doi: 10.1371/journal.pone.0086333
Su TP, Zhang L, Chung MY, Chen YS, Bi YM, Chou YH, et al. Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders. J Psychiatr Res. 2009;43:1078–85.
pubmed: 19380152
doi: 10.1016/j.jpsychires.2009.03.010
Schur RR, Boks MP, Rutten BPF, Daskalakis NP, de Nijs L, van Zuiden M, et al. Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment. Transl Psychiatry. 2017;7:e1181.
pubmed: 28742078
pmcid: 5538126
doi: 10.1038/tp.2017.150
Gonzalez Ramirez C, Villavicencio Queijeiro A, Jimenez Morales S, Barcenas Lopez D, Hidalgo Miranda A, Ruiz Chow A, et al. The NR3C1 gene expression is a potential surrogate biomarker for risk and diagnosis of posttraumatic stress disorder. Psychiatry Res. 2020;284:112797.
pubmed: 31982660
doi: 10.1016/j.psychres.2020.112797
Labonte B, Azoulay N, Yerko V, Turecki G, Brunet A. Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Transl Psychiatry. 2014;4:e368.
pubmed: 24594779
pmcid: 3966043
doi: 10.1038/tp.2014.3
Rice L, Waters CE, Eccles J, Garside H, Sommer P, Kay P, et al. Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor. J Endocrinol 2008;198:499–509.
pubmed: 18583474
pmcid: 2518725
doi: 10.1677/JOE-08-0019
Guintivano J, Brown T, Newcomer A, Jones M, Cox O, Maher BS, et al. Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors. Am J Psychiatry. 2014;171:1287–96.
pubmed: 25073599
pmcid: 7081376
doi: 10.1176/appi.ajp.2014.14010008
Boks MP, Rutten BP, Geuze E, Houtepen LC, Vermetten E, Kaminsky Z, et al. SKA2 methylation is involved in cortisol stress reactivity and predicts the development of post-traumatic stress disorder (PTSD) after military deployment. Neuropsychopharmacology. 2016;41:1350–6.
pubmed: 26361058
doi: 10.1038/npp.2015.286
Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34:S186–95.
pubmed: 19560279
doi: 10.1016/j.psyneuen.2009.05.021
Levy-Gigi E, Szabo C, Kelemen O, Keri S. Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy. Biol Psychiatry. 2013;74:793–800.
pubmed: 23856297
doi: 10.1016/j.biopsych.2013.05.017
Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol Psychiatry. 2009;66:708–11.
pubmed: 19393990
doi: 10.1016/j.biopsych.2009.02.034
Sarapas C, Cai G, Bierer LM, Golier JA, Galea S, Ising M, et al. Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks. Dis Markers. 2011;30:101–10.
pubmed: 21508514
pmcid: 3825240
doi: 10.1155/2011/328054
Szabo C, Kelemen O, Keri S. Changes in FKBP5 expression and memory functions during cognitive-behavioral therapy in posttraumatic stress disorder: a preliminary study. Neurosci Lett. 2014;569:116–20.
pubmed: 24704382
doi: 10.1016/j.neulet.2014.03.059
Kuan PF, Waszczuk MA, Kotov R, Clouston S, Yang X, Singh PK, et al. Gene expression associated with PTSD in World Trade Center responders: An RNA sequencing study. Transl Psychiatry. 2017;7:1297.
pubmed: 29249826
pmcid: 5802695
doi: 10.1038/s41398-017-0050-1
Kuan PF, Yang X, Clouston S, Ren X, Kotov R, Waszczuk M, et al. Cell type-specific gene expression patterns associated with posttraumatic stress disorder in World Trade Center responders. Transl Psychiatry. 2019;9:1.
pubmed: 30664621
pmcid: 6341096
doi: 10.1038/s41398-018-0355-8
Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16:33–41.
pubmed: 23201972
doi: 10.1038/nn.3275
Yin H, Galfalvy H, Pantazatos SP, Huang YY, Rosoklija GB, Dwork AJ, et al. Glucocorticoid receptor-related genes: genotype and brain gene expression relationships to suicide and major depressive disorder. Depress Anxiety. 2016;33:531–40.
pubmed: 27030168
pmcid: 4889464
doi: 10.1002/da.22499
Watkeys OJ, Kremerskothen K, Quide Y, Fullerton JM, Green MJ. Glucocorticoid receptor gene (NR3C1) DNA methylation in association with trauma, psychopathology, transcript expression, or genotypic variation: a systematic review. Neurosci Biobehav Rev. 2018;95:85–122.
pubmed: 30176278
doi: 10.1016/j.neubiorev.2018.08.017
Katrinli S, Oliveira NCS, Felger JC, Michopoulos V, Smith AK. The role of the immune system in posttraumatic stress disorder. Transl Psychiatry. 2022;12:313.
pubmed: 35927237
pmcid: 9352784
doi: 10.1038/s41398-022-02094-7
DePierro J, Lepow L, Feder A, Yehuda R. Translating molecular and neuroendocrine findings in posttraumatic stress disorder and resilience to novel therapies. Biol Psychiatry. 2019;86:454–63.
pubmed: 31466562
pmcid: 6907400
doi: 10.1016/j.biopsych.2019.07.009
Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002–12.
pubmed: 26544749
doi: 10.1016/S2215-0366(15)00309-0
Hori H, Kim Y. Inflammation and post-traumatic stress disorder. Psychiatry Clin Neurosci. 2019;73:143–53.
pubmed: 30653780
doi: 10.1111/pcn.12820
Gupta S, Guleria RS. Involvement of nuclear factor-kappaB in inflammation and neuronal plasticity associated with post-traumatic stress disorder. Cells. 2022;11:2034.
pubmed: 35805118
pmcid: 9265339
doi: 10.3390/cells11132034
Edmondson D, von Kanel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiatry. 2017;4:320–9.
pubmed: 28109646
pmcid: 5499153
doi: 10.1016/S2215-0366(16)30377-7
Boscarino JA. A prospective study of PTSD and early-age heart disease mortality among Vietnam veterans: implications for surveillance and prevention. Psychosom Med. 2008;70:668–76.
pubmed: 18596248
pmcid: 3552245
doi: 10.1097/PSY.0b013e31817bccaf
Daskalakis NP, Cohen H, Cai G, Buxbaum JD, Yehuda R. Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes. Proc Natl Acad Sci USA. 2014;111:13529–34.
pubmed: 25114262
pmcid: 4169965
doi: 10.1073/pnas.1401660111
Zaba M, Kirmeier T, Ionescu IA, Wollweber B, Buell DR, Gall-Kleebach DJ, et al. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients. Psychoneuroendocrinology. 2015;55:102–15.
pubmed: 25745955
doi: 10.1016/j.psyneuen.2015.02.005
Gadek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J. Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharm Rep. 2013;65:1655–62.
doi: 10.1016/S1734-1140(13)71527-5
Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60.
pubmed: 29184215
pmcid: 5726568
doi: 10.1038/s41593-017-0010-3
Borsini A, Zunszain PA, Thuret S, Pariante CM. The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci. 2015;38:145–57.
pubmed: 25579391
doi: 10.1016/j.tins.2014.12.006
Van Moortel L, Gevaert K, De Bosscher K. Improved glucocorticoid receptor ligands: fantastic beasts, but how to find them? Front Endocrinol (Lausanne). 2020;11:559673.
pubmed: 33071974
doi: 10.3389/fendo.2020.559673
Florido A, Velasco ER, Monari S, Cano M, Cardoner N, Sandi C, et al. Glucocorticoid-based pharmacotherapies preventing PTSD. Neuropharmacology. 2023;224:109344.
pubmed: 36402246
doi: 10.1016/j.neuropharm.2022.109344
Dunlop BW, Wong A. The hypothalamic-pituitary-adrenal axis in PTSD: pathophysiology and treatment interventions. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:361–79.
pubmed: 30342071
doi: 10.1016/j.pnpbp.2018.10.010