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01.08.2013 | Original Paper

HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter

verfasst von: Jeroen Melief, Stella J. de Wit, Corbert G. van Eden, Charlotte Teunissen, Jörg Hamann, Bernard M. Uitdehaag, Dick Swaab, Inge Huitinga

Erschienen in: Acta Neuropathologica | Ausgabe 2/2013

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Abstract

The hypothalamus–pituitary–adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro-inflammatory genes, such as tumor necrosis factor-α. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity.

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Baranzini SE, Srinivasan R, Khankhanian P, Okuda DT, Nelson SJ, Matthews PM, Hauser SL, Oksenberg JR, Pelletier D (2010) Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis. Brain 133(9):2603–2611PubMedCrossRef

Bergamaschi R (2007) Prognostic factors in multiple sclerosis. Int Rev Neurobiol 79(0074–7742 (Linking)):423–447PubMedCrossRef

Bergmeyer HU (1974) Methods of enzymatic analysis. Academic Press, New York

Bhavsar PK, Sukkar MB, Khorasani N, Lee K-Y, Chung KF (2008) Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-κB. FASEB J 22(6):1807–1816PubMedCrossRef

Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Brück W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123(Pt 6):1174–1183PubMedCrossRef

Butzkueven H, Zhang J-G, Soilu-Hanninen M et al (2002) LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 8(6):613–619PubMedCrossRef

Cao W, Yang Y, Wang Z et al (2011) Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Immunity 35(2):273–284PubMedCrossRef

Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924PubMedCrossRef

Chesnokova V, Melmed S (2000) Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation. Endocrinology 141(11):4032–4040PubMedCrossRef

10.

Deverman BE, Patterson PH (2012) Exogenous leukemia inhibitory factor stimulates oligodendrocyte progenitor cell proliferation and enhances hippocampal remyelination. J Neurosci 32(6):2100–2109PubMedCrossRef

11.

Erkut ZA, Endert E, Huitinga I, Swaab DF (2002) Cortisol is increased in postmortem cerebrospinal fluid of multiple sclerosis patients: relationship with cytokines and sepsis. Mult Scler 8(3):229–236PubMedCrossRef

12.

Erkut ZA, Klooker T, Endert E, Huitinga I, Swaab DF (2004) Stress of dying is not suppressed by high-dose morphine or by dementia. Neuropsychopharmacology 29(1):152–157PubMedCrossRef

13.

Evanson NK, Van H, Herman JP (2009) GluR5-mediated glutamate signaling regulates hypothalamo–pituitary–adrenocortical stress responses at the paraventricular nucleus and median eminence. Psychoneuroendocrinology 34(9):1370–1379PubMedCrossRef

14.

Fabriek BO, van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM, van den Berg TK, De Groot CJ, Van D, Dijkstra CD (2005) CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51(4):297–305PubMedCrossRef

15.

Fassbender K, Schmidt R, Mossner R, Kischka U, Kuhnen J, Schwartz A, Hennerici M (1998) Mood disorders and dysfunction of the hypothalamic–pituitary–adrenal axis in multiple sclerosis: association with cerebral inflammation. Arch Neurol 55(1):66–72PubMedCrossRef

16.

Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132(Pt 5):1175–1189PubMedCrossRef

17.

Gladwin MT, Kanias T, Kim-Shapiro DB (2012) Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. J Clin Invest 122(4):1205–1208PubMedCrossRef

18.

Gold SM, Krüger S, Ziegler KJ, Krieger T, Schulz K-H, Otte C, Heesen C (2011) Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J Neurol Neurosurg Psychiatr 82(7):814–818PubMedCrossRef

19.

Gold SM, Raji A, Huitinga I, Wiedemann K, Schulz KH, Heesen C (2005) Hypothalamo–pituitary–adrenal axis activity predicts disease progression in multiple sclerosis. J Neuroimmunol 165(1–2):186–191PubMedCrossRef

20.

Grasser A, Moller A, Backmund H, Yassouridis A, Holsboer F (1996) Heterogeneity of hypothalamic–pituitary–adrenal system response to a combined dexamethasone-CRH test in multiple sclerosis. Exp Clin Endocrinol Diabetes 104(1):31–37PubMedCrossRef

21.

Heesen C, Gold SM, Raji A, Wiedemann K, Schulz KH (2002) Cognitive impairment correlates with hypothalamo–pituitary–adrenal axis dysregulation in multiple sclerosis. Psychoneuroendocrinology 27(4):505–517PubMedCrossRef

22.

Heidbrink C, Hausler SF, Buttmann M et al (2010) Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis. Brain Behav Immun 24(6):975–984PubMedCrossRef

23.

Hennings JM, Owashi T, Binder EB et al (2009) Clinical characteristics and treatment outcome in a representative sample of depressed inpatients—findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res 43(3):215–229PubMedCrossRef

24.

Herman JP, Cullinan WE, Ziegler DR, Tasker JG (2002) Role of the paraventricular nucleus microenvironment in stress integration. Eur J Neurosci 16(3):381–385PubMedCrossRef

25.

Herman JP, Tasker JG, Ziegler DR, Cullinan WE (2002) Local circuit regulation of paraventricular nucleus stress integration: glutamate-GABA connections. Pharmacol Biochem Behav 71(3):457–468PubMedCrossRef

26.

Honda M, Nakagawa S, Hayashi K, Kitagawa N, Tsutsumi K, Nagata I, Niwa M (2006) Adrenomedullin improves the blood–brain barrier function through the expression of claudin-5. Cell Mol Neurobiol 26(2):109–118PubMedCrossRef

27.

Huitinga I, Erkut ZA, van Beurden D, Swaab DF (2004) Impaired hypothalamus–pituitary–adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions. Ann Neurol 55(1):37–45PubMedCrossRef

28.

Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL, Fields RD (2006) Astrocytes promote myelination in response to electrical impulses. Neuron 49(6):823–832PubMedCrossRef

29.

Koning N, Bo L, Hoek RM, Huitinga I (2007) Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol 62(5):504–514PubMedCrossRef

30.

Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409(6817):198–201PubMedCrossRef

31.

MacPhee IA, Antoni FA, Mason DW (1989) Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med 169(2):431–445PubMedCrossRef

32.

Melief J, Koning N, Schuurman KG, Van De Garde MD, Smolders J, Hoek RM, Van EM, Hamann J, Huitinga I (2012) Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia. doi:10.1002/glia.22370 PubMed

33.

Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos GP, Sternberg EM, Gold PW (1994) Multiple sclerosis is associated with alterations in hypothalamic–pituitary–adrenal axis function. J Clin Endocrinol Metab 79(3):848–853PubMedCrossRef

34.

Miller DH, Leary SM (2007) Primary-progressive multiple sclerosis. Lancet Neurol 6(10):903–912PubMedCrossRef

35.

Miller DH, Thompson AJ, Morrissey SP, MacManus DG, Moore SG, Kendall BE, Moseley IF, McDonald WI (1992) High dose steroids in acute relapses of multiple sclerosis: MRI evidence for a possible mechanism of therapeutic effect. J Neurol Neurosurg Psychiatry 55(6):450–453PubMedCrossRef

36.

Miyashita K, Itoh H, Arai H et al (2006) The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. Endocrinology 147(4):1642–1653PubMedCrossRef

37.

Moestrup SK, Møller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 36(5):347–354PubMedCrossRef

38.

Müller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ, Holsboer F, Swaab DF (2001) Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci 14(10):1603–1612PubMedCrossRef

39.

Penninx BWJH, Beekman ATF, Bandinelli S, Corsi AM, Bremmer M, Hoogendijk WJ, Guralnik JM, Ferrucci L (2007) Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the hypothalamo–pituitary–adrenal axis. Am J Geriatr Psychiatry 15(6):522–529PubMedCrossRef

40.

Perretti M, D’Acquisto F (2009) Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 9(1):62–70PubMedCrossRef

41.

Polman CH, Uitdehaag BM (2000) Drug treatment of multiple sclerosis. West J Med 173(6):398–402PubMedCrossRef

42.

Reder AT, Lowy MT, Meltzer HY, Antel JP (1987) Dexamethasone suppression test abnormalities in multiple sclerosis: relation to ACTH therapy. Neurology 37(5):849–853PubMedCrossRef

43.

Reder AT, Makowiec RL, Lowy MT (1994) Adrenal size is increased in multiple sclerosis. Arch Neurol 51(2):151–154PubMedCrossRef

44.

Runmarker B, Andersen O (1993) Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 116(Pt 1) (0006–8950 (Linking)):117–134

45.

Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS Jr (1995) Characterization of mechanisms involved in transrepression of NF-κB by activated glucocorticoid receptors. Mol Cell Biol 15(2):943–953PubMed

46.

Schumann EM, Kumpfel T, Then Bergh F, Trenkwalder C, Holsboer F, Auer DP (2002) Activity of the hypothalamic–pituitary–adrenal axis in multiple sclerosis: correlations with gadolinium-enhancing lesions and ventricular volume. Ann Neurol 51(6):763–767PubMedCrossRef

47.

Stefferl A, Storch MK, Linington C, Stadelmann C, Lassmann H, Pohl T, Holsboer F, Tilders FJ, Reul JM (2001) Disease progression in chronic relapsing experimental allergic encephalomyelitis is associated with reduced inflammation-driven production of corticosterone. Endocrinology 142(8):3616–3624PubMedCrossRef

48.

Stetler C, Miller GE (2011) Depression and hypothalamic–pituitary–adrenal activation: a quantitative summary of four decades of research. Psychosom Med 73(2):114–126PubMedCrossRef

49.

Talero E, Di Paola R, Mazzon E, Esposito E, Motilva V, Cuzzocrea S (2012) Anti-inflammatory effects of adrenomedullin on acute lung injury induced by Carrageenan in mice. Mediators Inflamm 2012:717851PubMed

50.

Teunissen CE, Lacobaeus E, Khademi M et al (2009) Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology 72(15):1322–1329PubMedCrossRef

51.

Then Bergh F, Grasser A, Trenkwalder C, Backmund H, Holsboer F, Rupprecht R (1999) Binding characteristics of the glucocorticoid receptor in peripheral blood lymphocytes in multiple sclerosis. J Neurol 246(4):292–298PubMedCrossRef

52.

Then Bergh F, Kumpfel T, Trenkwalder C, Rupprecht R, Holsboer F (1999) Dysregulation of the hypothalamo–pituitary–adrenal axis is related to the clinical course of MS. Neurology 53(4):772–777PubMedCrossRef

53.

Thompson PM, Bernardo CG, Cruz DA, Ketchum NS, Michalek JE (2013) Concordance of psychiatric symptom ratings between a subject and informant, relevancy to post-mortem research. Transl Psychiatry 3:e214PubMedCrossRef

54.

Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM (1989) Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci 9(5):1705–1711PubMed

55.

Vanderlocht J, Hellings N, Hendriks JJA, Vandenabeele F, Moreels M, Buntinx M, Hoekstra D, Antel JP, Stinissen P (2006) Leukemia inhibitory factor is produced by myelin-reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor-alpha-induced oligodendrocyte apoptosis. J Neurosci Res 83(5):763–774PubMedCrossRef

56.

Varga G, Ehrchen J, Tsianakas A, Tenbrock K, Rattenholl A, Seeliger S, Mack M, Roth J, Sunderkoetter C (2008) Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells. J Leukoc Biol 84(3):644–650PubMedCrossRef

57.

Van Veen T, Nielsen J, Berkhof J et al (2007) CCL5 and CCR5 genotypes modify clinical, radiological and pathological features of multiple sclerosis. J Neuroimmunol 190(1–2):157–164PubMedCrossRef

58.

Van Winsen LM, Manenschijn L, van Rossum EF, Crusius JB, Koper JW, Polman CH, Uitdehaag BM (2009) A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis. J Clin Endocrinol Metab 94(6):2110–2114PubMedCrossRef

59.

Ziegler DR, Cullinan WE, Herman JP (2005) Organization and regulation of paraventricular nucleus glutamate signaling systems: N-methyl-d-aspartate receptors. J Comp Neurol 484(1):43–56PubMedCrossRef

60.

Zwadlo-Klarwasser G, Bent S, Haubeck HD, Sorg C, Schmutzler W (1990) Glucocorticoid-induced appearance of the macrophage subtype RM 3/1 in peripheral blood of man. Int Arch Allergy Appl Immunol 91(2):175–180PubMedCrossRef

Titel: HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter
verfasst von: Jeroen Melief
Stella J. de Wit
Corbert G. van Eden
Charlotte Teunissen
Jörg Hamann
Bernard M. Uitdehaag
Dick Swaab
Inge Huitinga
Publikationsdatum: 01.08.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 2/2013
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1140-7

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HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter

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