Dexamethasone Induces a Specific Form of Ramified Dysfunctional Microglia

  • Min-Jung Park
  • Hyun-Sun Park
  • Min-Jung You
  • Jongman Yoo
  • Seung Hyun Kim
  • Min-Soo Kwon


The functional status of dynamic microglial cells plays an important role in maintaining homeostasis of microenvironment in CNS. In a previous study, we reported that microglia phenotype might be involved in stress vulnerability and depression recurrence. Here, we aimed to clarify a character of microglia exposed persistently to glucocorticoid (GC), which is representative a stress hormone, in primary cultured microglial cells. Five nanomolars of dexamethasone (DEX, GC agonist) for 72 h decreased CX3CR1 and CD200R expression and induced ramified form of microglial cells in similar morphology to in vivo resident microglia. However, the ramified form of microglia did not increase microglia signature genes such as P2RY12, OLFML3, TMEM119, and TGFBR1. In addition, DEX-treated microglia showed a reduction of phagocytosis function, pro-and anti-inflammatory cytokine production, and cell proliferation. DEX washout did not restore these changes. Based on transcriptomic analysis and functional characters of DEX-treated microglia, we performed senescence-associated beta-galactosidase (SA-β gal) assay in DEX-treated microglia and DEX-treated microglia showed more SA-β gal activity with alteration of cell cycle-related genes. Thus, our results suggest that DEX can induce a specific phenotype of microglia (like-senescence).


Microglia Stress hormone Depression Senescence 


Funding Information

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1D1A1B03029554).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6(6):463–475CrossRefPubMedGoogle Scholar
  2. 2.
    Schneiderman N, Ironson G, Siegel SD (2005) Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 1:607–628CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201CrossRefPubMedGoogle Scholar
  4. 4.
    Kato TA, Hayakawa K, Monji A, Kanba S (2013) Missing and possible link between neuroendocrine factors, neuropsychiatric disorders, and microglia. Front Integr Neurosci 7(53):1–16Google Scholar
  5. 5.
    Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38(10):637–658CrossRefPubMedGoogle Scholar
  6. 6.
    Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK et al (2014) Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81(5):1009–1023CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5):300–312CrossRefPubMedGoogle Scholar
  8. 8.
    Nayak D, Roth TL, McGavern DB (2014) Microglia development and function. Annu Rev Immunol 32:367–402CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170CrossRefPubMedGoogle Scholar
  10. 10.
    Casano AM, Peri F (2015) Microglia: multitasking specialists of the brain. Dev Cell 32(4):469–477CrossRefPubMedGoogle Scholar
  11. 11.
    Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11(11):775–787CrossRefPubMedGoogle Scholar
  12. 12.
    Michell-Robinson MA, Touil H, Healy LM, Owen DR, Durafourt BA, Bar-Or A, Antel JP, Moore CS (2015) Roles of microglia in brain development, tissue maintenance and repair. Brain 138(Pt 5):1138–1159CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29(2):68–74CrossRefPubMedGoogle Scholar
  14. 14.
    Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8):987–991CrossRefPubMedGoogle Scholar
  15. 15.
    Han A, Yeo H, Park MJ, Kim SH, Choi HJ, Hong CW, Kwon MS (2015) IL-4/10 prevents stress vulnerability following imipramine discontinuation. J Neuroinflammation 12:197CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang DR, Kidd G et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924CrossRefPubMedGoogle Scholar
  17. 17.
    Giulian D, Baker TJ (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci 6(8):2163–2178CrossRefPubMedGoogle Scholar
  18. 18.
    Kim CH, Cheng SL, Kim GS (1999) Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss. J Endocrinol 162(3):371–379CrossRefPubMedGoogle Scholar
  19. 19.
    Aden P, Paulsen RE, Maehlen J, Loberg EM, Goverud IL, Liestol K et al (2011) Glucocorticoids dexamethasone and hydrocortisone inhibit proliferation and accelerate maturation of chicken cerebellar granule neurons. Brain Res 1418:32–41CrossRefPubMedGoogle Scholar
  20. 20.
    Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP et al (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4(2):385–401CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143CrossRefPubMedGoogle Scholar
  23. 23.
    Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, el Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12):1896–1905CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705CrossRefPubMedGoogle Scholar
  25. 25.
    Caldeira C, Oliveira AF, Cunha C, Vaz AR, Falcao AS, Fernandes A et al (2014) Microglia change from a reactive to an age-like phenotype with the time in culture. Front Cell Neurosci 8:152CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wong WT (2013) Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci 7:22PubMedPubMedCentralGoogle Scholar
  27. 27.
    Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 15(7):482–496CrossRefPubMedGoogle Scholar
  28. 28.
    Young AR, Narita M (2010) Connecting autophagy to senescence in pathophysiology. Curr Opin Cell Biol 22(2):234–240CrossRefPubMedGoogle Scholar
  29. 29.
    Bell-Temin H, Culver-Cochran AE, Chaput D, Carlson CM, Kuehl M, Burkhardt BR, Bickford PC, Liu B et al (2015) Novel molecular insights into classical and alternative activation states of microglia as revealed by stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics. Mol Cell Proteomics 14(12):3173–3184CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL et al (2017) TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170(4):649–63Google Scholar
  31. 31.
    Yeh FL, Hansen DV, Sheng M (2017) TREM2, microglia, and neurodegenerative diseases. Trends Mol Med 23(6):512–533CrossRefPubMedGoogle Scholar
  32. 32.
    Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10(6):538–544CrossRefPubMedGoogle Scholar
  33. 33.
    O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N et al (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14(5):511–522CrossRefPubMedGoogle Scholar
  34. 34.
    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P (2011) Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A 108(22):9262–9267CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Browning CH (1996) Nonsteroidal anti-inflammatory drugs and severe psychiatric side effects. Int J Psychiatry Med 26(1):25–34CrossRefPubMedGoogle Scholar
  37. 37.
    Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, Maier SF, Yirmiya R (2014) Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry 19(6):699–709CrossRefPubMedGoogle Scholar
  38. 38.
    Miller GE, Cohen S, Ritchey AK (2002) Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol 21(6):531–541CrossRefPubMedGoogle Scholar
  39. 39.
    Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8(9):729–740CrossRefPubMedGoogle Scholar
  40. 40.
    Patschan S, Chen J, Polotskaia A, Mendelev N, Cheng J, Patschan D, Goligorsky MS (2008) Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells. Am J Physiol Heart Circ Physiol 294(3):H1119–H1129CrossRefPubMedGoogle Scholar
  41. 41.
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Troncoso R, Paredes F, Parra V, Gatica D, Vasquez-Trincado C, Quiroga C et al (2014) Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance. Cell Cycle 13(14):2281–2295CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Xue E, Zhang Y, Song B, Xiao J, Shi Z (2016) Effect of autophagy induced by dexamethasone on senescence in chondrocytes. Mol Med Rep 14(4):3037–3044CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39(1):19–34CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR, Veras MM, Pereira TF et al (2017) Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci 20(8):1162–1171CrossRefPubMedGoogle Scholar
  46. 46.
    Maher FO, Martin DS, Lynch MA (2004) Increased IL-1beta in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase. Neurobiol Aging 25(6):795–806CrossRefPubMedGoogle Scholar
  47. 47.
    Nolan Y, Maher FO, Martin DS, Clarke RM, Brady MT, Bolton AE, Mills KHG, Lynch MA (2005) Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus. J Biol Chem 280(10):9354–9362CrossRefPubMedGoogle Scholar
  48. 48.
    Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9(4):183–192CrossRefPubMedGoogle Scholar
  49. 49.
    Sorrells SF, Sapolsky RM (2007) An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 21(3):259–272CrossRefPubMedGoogle Scholar
  50. 50.
    Gomes JA, Stevens RD, Lewin JJ 3rd, Mirski MA, Bhardwaj A (2005) Glucocorticoid therapy in neurologic critical care. Crit Care Med 33(6):1214–1224CrossRefPubMedGoogle Scholar
  51. 51.
    Sapolsky RM, Pulsinelli WA (1985) Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 229(4720):1397–1400CrossRefPubMedGoogle Scholar
  52. 52.
    Dinkel K, MacPherson A, Sapolsky RM (2003) Novel glucocorticoid effects on acute inflammation in the CNS. J Neurochem 84(4):705–716CrossRefPubMedGoogle Scholar
  53. 53.
    Sarlus H, Heneka MT (2017) Microglia in Alzheimer’s disease. J Clin Invest 127(9):3240–3249CrossRefPubMedGoogle Scholar
  54. 54.
    Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119(1):89–105CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, School of MedicineCHA UniversitySeongnam-siRepublic of Korea
  2. 2.Department of Microbiology and School of MedicineCHA UniversitySeongnam-siRepublic of Korea
  3. 3.Cell Therapy Center and Department of Neurology, College of MedicineHanyang UniversitySeoulRepublic of Korea

Personalised recommendations