Top

Journal of Neuroinflammation

Published in:

Open Access 01-12-2016 | Research

Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury

Authors: Tingting Dong, Liang Zhi, Brijesh Bhayana, Mei X. Wu

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Acute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Neuroinflammation has been regarded both beneficial and detrimental, probably in a time-dependent fashion.

Methods

To address a role for neuroinflammation in brain injury, C57BL/6 mice were subjected to a closed head mild TBI (mTBI) by a standard controlled cortical impact, along with or without treatment of sphingosine 1-phosphate (S1P) or rolipram, after which the brain tissue of the impact site was evaluated for cell morphology via histology, inflammation by qRT-PCR and T cell staining, and cell death with Caspase-3 and TUNEL staining. Circulating lymphocytes were quantified by flow cytometry, and plasma hydrocortisone was analyzed by LC-MS/MS. To investigate the mechanism whereby cortisol lowered the number of peripheral T cells, T cell egress was tracked in lymph nodes by intravital confocal microscopy after hydrocortisone administration.

Results

We detected a decreased number of circulating lymphocytes, in particular, T cells soon after mTBI, which was inversely correlated with a transient and robust increase of plasma cortisol. The transient lymphocytopenia might be caused by cortisol in part via a blockade of lymphocyte egress as demonstrated by the ability of cortisol to inhibit T cell egress from the secondary lymphoid tissues. Moreover, exogenous hydrocortisone severely suppressed periphery lymphocytes in uninjured mice, whereas administering an egress-promoting agent S1P normalized circulating T cells in mTBI mice and increased T cells in the injured brain. Likewise, rolipram, a cAMP phosphodiesterase inhibitor, was also able to elevate cAMP levels in T cells in the presence of hydrocortisone in vitro and abrogate the action of cortisol in mTBI mice. The investigation demonstrated that the number of circulating T cells in the early phase of TBI was positively correlated with T cell infiltration and inflammatory responses as well as cell death at the cerebral cortex and hippocampus beneath the impact site.

Conclusions

Decreases in intracellular cAMP might be part of the mechanism behind cortisol-mediated blockade of T cell egress. The study argues strongly for a protective role of cortisol-induced immune suppression in the early stage of TBI.

Selassie AW, Zaloshnja E, Langlois JA, Miller T, Jones P, Steiner C. Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabil. 2008;23(2):123–31.CrossRefPubMed

Bramlett HM, Dietrich WD. Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res. 2007;161:125–41.CrossRef

Marklund N, Bakshi A, Castelbuono DJ, Conte V, McIntosh TK. Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr Pharm Des. 2006;12(13):1645–80.CrossRefPubMed

Finnie JW. Neuroinflammation: beneficial and detrimental effects after traumatic brain injury. Inflammopharmacology. 2013;21(4):309–20.CrossRefPubMed

Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268–75.CrossRefPubMed

Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol. 2006;16(3):258–64.CrossRefPubMed

Zhang Q, Zhou C, Hamblin MR, Wu MX. Low-level laser therapy effectively prevents secondary brain injury induced by immediate early responsive gene X-1 deficiency. J Cereb Blood Flow Metab. 2014;34(8):1391–401.CrossRefPubMedPubMedCentral

Morganti-Kossman MC, Lenzlinger PM, Hans V, Stahel P, Csuka E, Ammann E, et al. Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol Psychiatry. 1997;2(2):133–6.CrossRefPubMed

Bradbury MW. The blood-brain barrier. Exp Physiol. 1993;78(4):453–72.CrossRefPubMed

10.

Cederberg D, Siesjo P. What has inflammation to do with traumatic brain injury? Childs Nerv Syst. 2010;26(2):221–6.CrossRefPubMed

11.

Clausen F, Lorant T, Lewen A, Hillered L. T lymphocyte trafficking: a novel target for neuroprotection in traumatic brain injury. J Neurotrauma. 2007;24(8):1295–307.CrossRefPubMed

12.

Santarsieri M, Niyonkuru C, McCullough EH, Dobos JA, Dixon CE, et al. Cerebrospinal fluid cortisol and progesterone profiles and outcomes prognostication after severe traumatic brain injury. J Neurotrauma. 2014;31(8):699–712.CrossRefPubMedPubMedCentral

13.

Wagner AK, McCullough EH, Niyonkuru C, Ozawa H, Loucks TL, et al. Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury. J Neurotrauma. 2011;28(6):871–88.CrossRefPubMedPubMedCentral

14.

Dong T, Zhang Q, Hamblin MR, Wu MX. Low-level light in combination with metabolic modulators for effective therapy of injured brain. J Cereb Blood Flow Metab. 2015;35(9):1435–44.CrossRefPubMed

15.

Zhi L, Kim P, Thompson BD, Pitsillides C, Bankovich AJ, Yun SH, et al. FTY720 blocks egress of T cells in part by abrogation of their adhesion on the lymph node sinus. J Immunol. 2011;187(5):2244–51.CrossRefPubMedPubMedCentral

16.

Kim P, Puoris’haag M, Cote D, Lin CP, Yun SH. In vivo confocal and multiphoton microendoscopy. J Biomed Opt. 2008;13(1):010501.CrossRefPubMedPubMedCentral

17.

Thompson BD, Jin Y, Wu KH, Colvin RA, Luster AD, Birnbaumer L, et al. Inhibition of G alpha i2 activation by G alpha i3 in CXCR3-mediated signaling. J Biol Chem. 2007;282(13):9547–55.CrossRefPubMed

18.

Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.CrossRefPubMed

19.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335(1):2–13.CrossRefPubMedPubMedCentral

20.

Bolton PM, Kirov SM, Donald KJ. The effects of major and minor trauma on lymphocyte kinetics in mice. Aust J Exp Biol Med Sci. 1979;57:479–92.CrossRefPubMed

21.

Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427(6972):355–60.CrossRefPubMed

22.

Graler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 2004;18(3):551–3.PubMed

23.

Kelso ML, Gendelman HE. Bridge between neuroimmunity and traumatic brain injury. Curr Pharm Des. 2014;20(26):4284–98.PubMedPubMedCentral

24.

Grigorova IL, Schwab SR, Phan TG, Pham TH, Okada T, Cyster JG. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol. 2009;10(1):58–65.CrossRefPubMed

25.

Wei SH, Rosen H, Matheu MP, Sanna MG, Wang SK, Jo E, et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat Immunol. 2005;6(12):1228–35.CrossRefPubMed

26.

Sinha RK, Park C, Hwang IY, Davis MD, Kehrl JH. B lymphocytes exit lymph nodes through cortical lymphatic sinusoids by a mechanism independent of sphingosine-1-phosphate-mediated chemotaxis. Immunity. 2009;30(3):434–46.CrossRefPubMedPubMedCentral

27.

Sensken SC, Nagarajan M, Bode C, Graler MH. Local inactivation of sphingosine 1-phosphate in lymph nodes induces lymphopenia. J Immunol. 2011;186(6):3432–40.CrossRefPubMed

28.

Schoettle RJ, Kochanek PM, Magargee MJ, Uhl MW, Nemoto EM. Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma. 1990;7(4):207–17.CrossRefPubMed

29.

Soares HD, Hicks RR, Smith D, McIntosh TK. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci. 1995;15(12):8223–33.PubMed

30.

Giulian D, Chen J, Ingeman JE, George JK, Noponen M. The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J Neurosci. 1989;9(12):4416–29.PubMed

31.

Holmin S, Mathiesen T, Shetye J, Biberfeld P. Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir (Wien). 1995;132(1-3):110–9.CrossRef

32.

Marklund N, Hillered L. Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here? Br J Pharmacol. 2011;164(4):1207–29.CrossRefPubMedPubMedCentral

33.

Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990;322(20):1405–11.CrossRefPubMed

34.

Bracken MB, Shepard MJ, Collins Jr WF, Holford TR, Baskin DS, Eisenberg HM, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study. J Neurosurg. 1992;76(1):23–31.CrossRefPubMed

35.

Chen X, Zhao Z, Chai Y, Luo L, Jiang R, Dong J, et al. Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats. Crit Care. 2013;17(5):R241.CrossRefPubMedPubMedCentral

36.

Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49(4):391–402. 402.CrossRefPubMed

37.

Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12(2):R61.CrossRefPubMedPubMedCentral

38.

Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007;27(11):1798–805.CrossRefPubMedPubMedCentral

39.

Fee D, Crumbaugh A, Jacques T, Herdrich B, Sewell D, Auerbach D, et al. Activated/effector CD4+ T cells exacerbate acute damage in the central nervous system following traumatic injury. J Neuroimmunol. 2003;136(1-2):54–66.CrossRefPubMed

40.

Wolf SA, Steiner B, Akpinarli A, Kammertoens T, Nassenstein C, Braun A, et al. CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol. 2009;182(7):3979–84.CrossRefPubMed

41.

De Kloet ER. Hormones and the stressed brain. Ann N Y Acad Sci. 2004;1018:1–15.CrossRefPubMed

42.

Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE. The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn. 2007;65(3):209–37.CrossRefPubMed

43.

O’Brien N, Jones ST, Williams DG, Cunningham HB, Moreno K, et al. Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies. J Lipid Res. 2009;50(11):2245–57.CrossRefPubMedPubMedCentral

44.

Brinkmann V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol. 2009;158(5):1173–82.CrossRefPubMedPubMedCentral

45.

Clark AR. Anti-inflammatory functions of glucocorticoid-induced genes. Mol Cell Endocrinol. 2007;275(1-2):79–97.CrossRefPubMed

46.

Reichardt HM, Schutz G. Glucocorticoid signalling—multiple variations of a common theme. Mol Cell Endocrinol. 1998;146(1-2):1–6.CrossRefPubMed

47.

Tuckermann JP, Kleiman A, Moriggl R, Spanbroek R, Neumann A, Illing A, et al. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J Clin Invest. 2007;117(5):1381–90.CrossRefPubMedPubMedCentral

48.

Cox JH, Ford WL. The migration of lymphocytes across specialized vascular endothelium. IV. Prednisolone acts at several points on the recirculation pathways of lymphocytes. Cell Immunol. 1982;66(2):407–22.CrossRefPubMed

49.

Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316(5822):295–8.CrossRefPubMed

50.

Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol. 2005;5(7):560–70.CrossRefPubMed

Title: Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury
Authors: Tingting Dong
Liang Zhi
Brijesh Bhayana
Mei X. Wu
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0663-y

ACC 2024 Congress

Springer Medicine

Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

IL-10 plays an important role in the control of inflammation but not in the bacterial burden in S. epidermidis CNS catheter infection

Gas1 up-regulation is inducible and contributes to cell apoptosis in reactive astrocytes in the substantia nigra of LPS and MPTP models

Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations in near-term ovine fetuses: a case for the afferent cholinergic anti-inflammatory pathway?

C-C motif chemokine ligand 20 regulates neuroinflammation following spinal cord injury via Th17 cell recruitment

Erratum to: Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells

Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques