Assessing the role of toll-like receptor in isolated, standard and enriched housing conditions

Autoři: Tahani K. Alshammari aff001;  Hajar Alghamdi aff002;  Thomas A. Green aff003;  Abdurahman Niazy aff004;  Lama Alkahdar aff001;  Nouf Alrasheed aff001;  Khalid Alhosaini aff001;  Mohammed Alswayyed aff005;  Ramesh Elango aff006;  Fernanda Laezza aff003;  Musaad A. Alshammari aff001;  Hazar Yacoub aff001
Působiště autorů: Department of Pharmacology and Toxicology, Pharmacy College, King Saud University, Riyadh, Saudi Arabia aff001;  Pharmacology & Toxicology Graduate Program, Pharmacy College, King Saud University, Riyadh, Saudi Arabia aff002;  Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States of America aff003;  Prince Naïf Bin Abdul-Aziz Health Research Center, King Saud University, Riyadh, Saudi Arabia aff004;  Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia aff005;  Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Depression is a common psychiatric disorder that has been poorly understood. Consequently, current antidepressant agents have clinical limitations. Until today, most have exhibited the slow onset of therapeutic action and, more importantly, their effect on remission has been minimal. Thus, the need to find new forms of therapeutic intervention is urgent. The inflammation hypothesis of depression is widely acknowledged and is one that theories the relationship between the function of the immune system and its contribution to the neurobiology of depression. In this research, we utilized an environmental isolation (EI) approach as a valid animal model of depression, employing biochemical, molecular, and behavioral studies. The aim was to investigate the anti-inflammatory effect of etanercept, a tumor necrosis factor-α inhibitor on a toll-like receptor 7 (TLR 7) signaling pathway in a depressive rat model, and compare these actions to fluoxetine, a standard antidepressant agent. The behavioral analysis indicates that depression-related symptoms are reduced after acute administration of fluoxetine and, to a lesser extent, etanercept, and are prevented by enriched environment (EE) housing conditions. Experimental studies were conducted by evaluating immobility time in the force swim test and pleasant feeling in the sucrose preference test. The mRNA expression of the TLR 7 pathway in the hippocampus showed that TLR 7, MYD88, and TRAF6 were elevated in isolated rats compared to the standard group, and that acute treatment with an antidepressant and anti-inflammatory drugs reversed these effects. This research indicates that stressful events have an impact on behavioral well-being, TLR7 gene expression, and the TLR7 pathway. We also found that peripheral administration of etanercept reduces depressive-like behaviour in isolated rats: this could be due to the indirect modulation of the TLR7 pathway and other TLRs in the brain. Furthermore, fluoxetine treatment reversed depressive-like behaviour and molecularly modulated the expression of TLR7, suggesting that fluoxetine exerts antidepressant effects partially by modulating the TLR7 signaling pathway.

Klíčová slova:

Antidepressants – Depression – Hippocampus – Immune receptor signaling – Inflammation – Rats – Sucrose – Toll-like receptors


1. Jia J, Le W. Molecular network of neuronal autophagy in the pathophysiology and treatment of depression. Neurosci Bull. 2015;31(4):427–34. doi: 10.1007/s12264-015-1548-2 26254058; PubMed Central PMCID: PMC5563719.

2. Saveanu RV, Nemeroff CB. Etiology of depression: genetic and environmental factors. Psychiatr Clin North Am. 2012;35(1):51–71. doi: 10.1016/j.psc.2011.12.001 22370490.

3. Mehta-Raghavan NS, Wert SL, Morley C, Graf EN, Redei EE. Nature and nurture: environmental influences on a genetic rat model of depression. Transl Psychiatry. 2016;6:e770. doi: 10.1038/tp.2016.28 27023176; PubMed Central PMCID: PMC4872452.

4. Garate I, Garcia-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR, et al. Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflammation. 2011;8:151. doi: 10.1186/1742-2094-8-151 22053929; PubMed Central PMCID: PMC3219571.

5. Brymer KJ, Romay-Tallon R, Allen J, Caruncho HJ, Kalynchuk LE. Exploring the Potential Antidepressant Mechanisms of TNFalpha Antagonists. Front Neurosci. 2019;13:98. Epub 2019/02/26. doi: 10.3389/fnins.2019.00098 30804748; PubMed Central PMCID: PMC6378555.

6. Vogelzangs N, de Jonge P, Smit JH, Bahn S, Penninx BW. Cytokine production capacity in depression and anxiety. Transl Psychiatry. 2016;6(5):e825. Epub 2016/06/01. doi: 10.1038/tp.2016.92 27244234; PubMed Central PMCID: PMC5070051.

7. Pandey GN, Rizavi HS, Ren X, Bhaumik R, Dwivedi Y. Toll-like receptors in the depressed and suicide brain. J Psychiatr Res. 2014;53:62–8. doi: 10.1016/j.jpsychires.2014.01.021 24565447; PubMed Central PMCID: PMC4004369.

8. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23(2):335–43. doi: 10.1038/mp.2016.167 27752078; PubMed Central PMCID: PMC5794896.

9. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229. Epub 2013/05/07. doi: 10.1016/j.neuroscience.2013.04.060 23644052; PubMed Central PMCID: PMC3741070.

10. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34. doi: 10.1038/nri.2015.5 26711676; PubMed Central PMCID: PMC5542678.

11. Haapakoski R, Ebmeier KP, Alenius H, Kivimaki M. Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances. Progress in neuro-psychopharmacology & biological psychiatry. 2016;66:63–72. doi: 10.1016/j.pnpbp.2015.11.012 26631274; PubMed Central PMCID: PMC4736094.

12. Lancaster GI, Khan Q, Drysdale P, Wallace F, Jeukendrup AE, Drayson MT, et al. The physiological regulation of toll-like receptor expression and function in humans. J Physiol. 2005;563(Pt 3):945–55. doi: 10.1113/jphysiol.2004.081224 15661814; PubMed Central PMCID: PMC1665604.

13. Rosenberger K, Derkow K, Dembny P, Kruger C, Schott E, Lehnardt S. The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration. J Neuroinflammation. 2014;11:166. doi: 10.1186/s12974-014-0166-7 25239168; PubMed Central PMCID: PMC4182775.

14. Carpenter S, Carlson T, Dellacasagrande J, Garcia A, Gibbons S, Hertzog P, et al. TRIL, a functional component of the TLR4 signaling complex, highly expressed in brain. J Immunol. 2009;183(6):3989–95. Epub 2009/08/28. doi: 10.4049/jimmunol.0901518 19710467.

15. Garate I, Garcia-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, et al. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation. 2014;11:8. doi: 10.1186/1742-2094-11-8 24410883; PubMed Central PMCID: PMC3897306.

16. Fischer CW, Liebenberg N, Elfving B, Lund S, Wegener G. Isolation-induced behavioural changes in a genetic animal model of depression. Behav Brain Res. 2012;230(1):85–91. doi: 10.1016/j.bbr.2012.01.050 22321459.

17. Sacre S, Medghalchi M, Gregory B, Brennan F, Williams R. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum. 2010;62(3):683–93. doi: 10.1002/art.27304 20131240.

18. Moncek F, Duncko R, Johansson BB, Jezova D. Effect of environmental enrichment on stress related systems in rats. Journal of neuroendocrinology. 2004;16(5):423–31. doi: 10.1111/j.1365-2826.2004.01173.x 15117335.

19. Boyko M, Kutz R, Grinshpun J, Zvenigorodsky V, Gruenbaum SE, Gruenbaum BF, et al. Establishment of an animal model of depression contagion. Behav Brain Res. 2015;281:358–63. doi: 10.1016/j.bbr.2014.12.017 25523029; PubMed Central PMCID: PMC4305483.

20. Green TA, Alibhai IN, Roybal CN, Winstanley CA, Theobald DE, Birnbaum SG, et al. Environmental enrichment produces a behavioral phenotype mediated by low cyclic adenosine monophosphate response element binding (CREB) activity in the nucleus accumbens. Biological psychiatry. 2010;67(1):28–35. doi: 10.1016/j.biopsych.2009.06.022 19709647; PubMed Central PMCID: PMC2860655.

21. Luedtke K, Bouchard SM, Woller SA, Funk MK, Aceves M, Hook MA. Assessment of depression in a rodent model of spinal cord injury. J Neurotrauma. 2014;31(12):1107–21. doi: 10.1089/neu.2013.3204 24564232; PubMed Central PMCID: PMC4062114.

22. Hernandez CM, Cortez I, Gu Z, Colón-Sáez JO, Lamb PW, Wakamiya M, et al. Research tool: validation of floxed α7 nicotinic acetylcholine receptor conditional knockout mice using in vitro and in vivo approaches. The Journal of Physiology. 2014;592(Pt 15):3201–14. doi: 10.1113/jphysiol.2014.272054 PMC4146370. 24879866

23. Alshammari MA, Alshammari TK, Laezza F. Improved Methods for Fluorescence Microscopy Detection of Macromolecules at the Axon Initial Segment. Frontiers in Cellular Neuroscience. 2016;10(5). doi: 10.3389/fncel.2016.00005 26909021

24. Zhang Y, Kong F, Crofton EJ, Dragosljvich SN, Sinha M, Li D, et al. Transcriptomics of Environmental Enrichment Reveals a Role for Retinoic Acid Signaling in Addiction. Front Mol Neurosci. 2016;9:119. doi: 10.3389/fnmol.2016.00119 27899881; PubMed Central PMCID: PMC5110542.

25. Vialou V, Robison AJ, LaPlant QC, Covington Iii HE, Dietz DM, Ohnishi YN, et al. ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nature Neuroscience. 2010;13:745. doi: 10.1038/nn.2551 20473292

26. Ito R, Robbins TW, Pennartz CM, Everitt BJ. Functional interaction between the hippocampus and nucleus accumbens shell is necessary for the acquisition of appetitive spatial context conditioning. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2008;28(27):6950–9. Epub 2008/07/04. doi: 10.1523/jneurosci.1615-08.2008 18596169; PubMed Central PMCID: PMC3844800.

27. Wallace DL, Han MH, Graham DL, Green TA, Vialou V, Iniguez SD, et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci. 2009;12(2):200–9. doi: 10.1038/nn.2257 19151710; PubMed Central PMCID: PMC2721778.

28. Veena J, Srikumar BN, Raju TR, Shankaranarayana Rao BS. Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats. Neurosci Lett. 2009;455(3):178–82. doi: 10.1016/j.neulet.2009.03.059 19429116.

29. Bayramgurler D, Karson A, Ozer C, Utkan T. Effects of long-term etanercept treatment on anxiety- and depression-like neurobehaviors in rats. Physiol Behav. 2013;119:145–8. doi: 10.1016/j.physbeh.2013.06.010 23769689.

30. Krugel U, Fischer J, Radicke S, Sack U, Himmerich H. Antidepressant effects of TNF-alpha blockade in an animal model of depression. J Psychiatr Res. 2013;47(5):611–6. doi: 10.1016/j.jpsychires.2013.01.007 23394815.

31. Sarkisova K, Folomkina AA. [Effect of selective serotonin reuptake inhibitor fluoxetine on symptoms of depression-like behavior in WAG/Rij rats]. Zh Vyssh Nerv Deiat Im I P Pavlova. 2010;60(1):98–108. 20352689.

32. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, et al. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008;5:15. doi: 10.1186/1742-2094-5-15 18477398; PubMed Central PMCID: PMC2412862.

33. Machado DG, Cunha MP, Neis VB, Balen GO, Colla A, Grando J, et al. Fluoxetine reverses depressive-like behaviors and increases hippocampal acetylcholinesterase activity induced by olfactory bulbectomy. Pharmacol Biochem Behav. 2012;103(2):220–9. doi: 10.1016/j.pbb.2012.08.024 22960127.

34. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367(9504):29–35. doi: 10.1016/S0140-6736(05)67763-X 16399150.

35. Chang R, Knox J, Chang J, Derbedrossian A, Vasilevko V, Cribbs D, et al. Blood-Brain Barrier Penetrating Biologic TNF-alpha Inhibitor for Alzheimer's Disease. Molecular pharmaceutics. 2017;14(7):2340–9. Epub 2017/05/19. doi: 10.1021/acs.molpharmaceut.7b00200 28514851.

36. Kerfoot SM, D'Mello C, Nguyen H, Ajuebor MN, Kubes P, Le T, et al. TNF-alpha-secreting monocytes are recruited into the brain of cholestatic mice. Hepatology (Baltimore, Md). 2006;43(1):154–62. Epub 2005/12/24. doi: 10.1002/hep.21003 16374849.

37. Brymer KJ, Fenton EY, Kalynchuk LE, Caruncho HJ. Peripheral Etanercept Administration Normalizes Behavior, Hippocampal Neurogenesis, and Hippocampal Reelin and GABAA Receptor Expression in a Preclinical Model of Depression. Frontiers in Pharmacology. 2018;9(121). doi: 10.3389/fphar.2018.00121 29515447

38. Campbell SJ, Jiang Y, Davis AEM, Farrands R, Holbrook J, Leppert D, et al. Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. Journal of Neurochemistry. 2007;103(6):2245–55. doi: 10.1111/j.1471-4159.2007.04928.x 17883399

39. Boado RJ, Hui EK, Lu JZ, Zhou QH, Pardridge WM. Selective targeting of a TNFR decoy receptor pharmaceutical to the primate brain as a receptor-specific IgG fusion protein. J Biotechnol. 2010;146(1–2):84–91. Epub 2010/01/27. doi: 10.1016/j.jbiotec.2010.01.011 20100527; PubMed Central PMCID: PMC2832096.

40. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453–62. Epub 2007/01/05. doi: 10.1002/glia.20467 17203472; PubMed Central PMCID: PMC2871685.

41. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008;5:45. Epub 2008/10/18. doi: 10.1186/1742-2094-5-45 18925972; PubMed Central PMCID: PMC2577641.

42. Kielian T. Overview of toll-like receptors in the CNS. Curr Top Microbiol Immunol. 2009;336:1–14. doi: 10.1007/978-3-642-00549-7_1 19688325; PubMed Central PMCID: PMC4234738.

43. O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13(6):453–60. Epub 2013/05/18. doi: 10.1038/nri3446 23681101.

44. Kenis G, Maes M. Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol. 2002;5(4):401–12. Epub 2002/12/06. doi: 10.1017/S1461145702003164 12466038.

45. Nan Z, Jin Z, Huijuan C, Tiezheng Z, Keyan C. Effects of TLR3 and TLR9 Signaling Pathway on Brain Protection in Rats Undergoing Sevoflurane Pretreatment during Cardiopulmonary Bypass. Biomed Res Int. 2017;2017:4286738. doi: 10.1155/2017/4286738 29445737; PubMed Central PMCID: PMC5763070.

46. Hanke ML, Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond). 2011;121(9):367–87. doi: 10.1042/CS20110164 21745188; PubMed Central PMCID: PMC4231819.

47. Sorensen LN, Reinert LS, Malmgaard L, Bartholdy C, Thomsen AR, Paludan SR. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J Immunol. 2008;181(12):8604–12. doi: 10.4049/jimmunol.181.12.8604 19050280.

48. Tauber SC, Ebert S, Weishaupt JH, Reich A, Nau R, Gerber J. Stimulation of Toll-like receptor 9 by chronic intraventricular unmethylated cytosine-guanine DNA infusion causes neuroinflammation and impaired spatial memory. J Neuropathol Exp Neurol. 2009;68(10):1116–24. doi: 10.1097/NEN.0b013e3181b7fde5 19918123.

49. Owens T. Toll-like receptors in neurodegeneration. Curr Top Microbiol Immunol. 2009;336:105–20. doi: 10.1007/978-3-642-00549-7_6 19688330.

50. Okun E, Griffioen K, Barak B, Roberts NJ, Castro K, Pita MA, et al. Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2010;107(35):15625–30. doi: 10.1073/pnas.1005807107 20713712; PubMed Central PMCID: PMC2932590.

51. Hung YY, Huang KW, Kang HY, Huang GY, Huang TL. Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder. Psychopharmacology (Berl). 2016;233(9):1707–14. doi: 10.1007/s00213-015-4087-7 26415953; PubMed Central PMCID: PMC4828490.

52. Xiang Y, Yan H, Zhou J, Zhang Q, Hanley G, Caudle Y, et al. The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage. PLoS One. 2015;10(4):e0123447. doi: 10.1371/journal.pone.0123447 25885582; PubMed Central PMCID: PMC4401452.

53. Hung YY, Kang HY, Huang KW, Huang TL. Association between toll-like receptors expression and major depressive disorder. Psychiatry Res. 2014;220(1–2):283–6. Epub 2014/08/27. doi: 10.1016/j.psychres.2014.07.074 25155940.

54. Roumestan C, Michel A, Bichon F, Portet K, Detoc M, Henriquet C, et al. Anti-inflammatory properties of desipramine and fluoxetine. Respir Res. 2007;8:35. Epub 2007/05/05. doi: 10.1186/1465-9921-8-35 17477857; PubMed Central PMCID: PMC1876225.

55. Lu Y, Ho CS, Liu X, Chua AN, Wang W, McIntyre RS, et al. Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression. PLoS One. 2017;12(10):e0186700. doi: 10.1371/journal.pone.0186700 29049348; PubMed Central PMCID: PMC5648231.

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