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Nervenheilkunde 2014; 33(11): 780-789
DOI: 10.1055/s-0038-1627746
Mikroglia
Schattauer GmbH

Mikroglia als Vermittler immuno-logischer Aspekte der Depression

Microglia mediate immunological aspects of depression
A. Friebe
1   Klinik für Psychiatrie, Psychotherapie und Präventivmedizin, LWL-Universitätsklinik der Ruhr-Universität Bochum
,
S. Wachholz
1   Klinik für Psychiatrie, Psychotherapie und Präventivmedizin, LWL-Universitätsklinik der Ruhr-Universität Bochum
,
M. Esslinger
1   Klinik für Psychiatrie, Psychotherapie und Präventivmedizin, LWL-Universitätsklinik der Ruhr-Universität Bochum
,
M. Schäfer
2   Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin, Kliniken Essen-Mitte, Essen
› Institutsangaben
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Publikationsverlauf

eingegangen am: 01. Juli 2014

angenommen am: 05. August 2014

Publikationsdatum:
24. Januar 2018 (online)

    Lizenzen und Reprints

Zusammenfassung

Eine Immunaktivierung geht häufig mit Verhaltensänderungen (sickness behavior) einher, die Teil der unspezifischen Immunantwort sind, über inflammatorische Zytokine gesteuert werden und durch veränderte Priorisierung von Aktivitäten zur erfolgreichen Immunabwehr beitragen. Bei chronischer Immunaktivität kann sich aus diesen Verhaltensänderungen ein depressives Syndrom entwickeln. Dieser Zusammenhang wurde anhand humaner Modelle (immunaktivierende Behandlung mit Interferon-alpha) bestätigt. Umgekehrt finden sich erhöhte Immunparameter auch bei primär depressiven Patienten und Studien zeigten antidepressive Effekte einer anti-inflammatorischen Add-on-Therapie. Psychischer Stress, der eine Aktivierung des peripheren Immunsystems bewirkt und Hauptrisikofaktor für die Entwicklung einer depressiven Episode ist, könnte hier als Bindeglied fungieren. Mikroglia sind an vorderster Front in inflammatorische Prozesse im ZNS involviert und parallel an der Aufrechterhaltung synaptischer Verbindungen beteiligt. Sie bilden eine wichtige Schnittstelle zwischen Inflammation und Neurotransmission. Sowohl inflammatorische Prozesse in der Peripherie als auch psychischer Stress führen zur Aktivierung von Mikroglia und triggern die Induktion eines pro-inflammatorischen, neurotoxischen Phänotyps. Freigesetzte Zytokine und neurotoxische Metabolite induzieren über vielfältige Mechanismen depressive Symptome und triggern degenerative Prozesse (Neuropilreduktion). Eine Beteiligung der Mikroglia in der Pathophysiologie der Depression wird vermutet.

Summary

An acute immune activation is accompanied by a change in behavior (sickness behavior), which is part of the innate immune response, develops under the control of inflammatory cytokines and contributes to a successful immune defense by changing prioritization of activities. In case of chronic immune activation, sickness behavior can turn into a depressive syndrome, which was confirmed in human models (immune activating therapy with Interferon alpha). Inflammatory parameters are also increased in primary depressed patients and clinical studies showed anti-depressive effects of an anti-inflammatory addon therapy. Psychological stress, which activates the peripheral immune system and is the main risk factor for a depressive episode, might serve as link for these observations. Microglia are involved as first line responders in inflammatory processes in the CNS and in the maintenance of synaptic connectivity. Thus, they serve as an important interface between inflammation and neurotransmission. Peripheral inflammation as well as psychological stress activates microglia and triggers a pro-inflammatory, neurotoxic phenotype. Released cytokines and neurotoxic metabolites induce depressive symptoms via diverse mechanisms and trigger degenerative processes (neuropil reduction). An involvement of microglia in the pathophysiology of depression is assumed.

Schlüsselwörter

Depression - Inflammation - Mikroglia - Zytokine

Keywords

Depression - inflammation - microglia - cytokines
 

  • Literatur

  • 1 Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe – a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005; 15 (04) 357-76.
    CrossrefPubMedGoogle Scholar
  • 2 Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry 2000; 157 (08) 1243-51.
    CrossrefPubMedGoogle Scholar
  • 3 Kendler KS, Thornton LM, Gardner CO. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 2001; 158 (04) 582-6.
    CrossrefPubMedGoogle Scholar
  • 4 Insel TR, Wang PS. The STAR*D trial: revealing the need for better treatments. Psychiatr Serv 2009; 60 (11) 1466-7.
    CrossrefPubMedGoogle Scholar
  • 5 Kent S, Bluthé RM, Kelley KW, Dantzer R. Sickness behavior as a new target for drug development. Trends Pharmacol Sci 1992; 13 (01) 24-8.
    CrossrefPubMedGoogle Scholar
  • 6 Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Annals of the New York Academy of Sciences 2001; 933: 222-34.
    PubMedGoogle Scholar
  • 7 Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain, Behavior, and Immunity 2007; 21 (02) 153-60.
    CrossrefPubMedGoogle Scholar
  • 8 Myers JS. Proinflammatory cytokines and sickness behavior: implications for depression and cancerrelated symptoms. Oncology Nursing Forum 2008; 35 (05) 802-7.
    CrossrefPubMedGoogle Scholar
  • 9 McCusker RH, Kelley KW. Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol 2013; 216 (Pt 1): 84-98.
    CrossrefPubMedGoogle Scholar
  • 10 Taché Y, Bernstein CN. Evidence for the role of the brain-gut axis in inflammatory bowel disease: depression as cause and effect?. Gastroenterology 2009; 136 (07) 2058-61.
    CrossrefPubMedGoogle Scholar
  • 11 Graff LA, Walker JR, Bernstein CN. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis 2009; 15 (07) 1105-18.
    CrossrefPubMedGoogle Scholar
  • 12 Kojima M. et al. Depression, inflammation, and pain in patients with rheumatois arthritis. Arthritis Rheum 2009; 61 (08) 1018-24.
    CrossrefPubMedGoogle Scholar
  • 13 Low CA, Cunningham AL, Kao AH, Krishnaswami S, Kuller LH, Wasko MC. Association between C-reactive protein and depressive symptoms in women with rheumatoid arthritis. Biol Psychol 2009; 81 (02) 131-4.
    CrossrefPubMedGoogle Scholar
  • 14 Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology 2013; 52: 2136-2148.
    CrossrefPubMedGoogle Scholar
  • 15 Thombs BD, Hudson M, Taillefer SS, Baron M. Canadian Scleroderma Research Group. Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis. Arthritis Rheum 2008; 59 (04) 504-9.
    CrossrefPubMedGoogle Scholar
  • 16 Maneeton B, Maneeton N, Louthrenoo W. Prevalence and predictors of depression in patients with systemic lupus erythematosus: a cross-sectional study. Neuropsychiatr Dis Treat 2013; 09: 799-804.
    Google Scholar
  • 17 Dowlatshahi EA, Wakkee M, Arends LR, Nijsten T. The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Invest Dermatol 2014; 134 (06) 1542-51.
    CrossrefPubMedGoogle Scholar
  • 18 McDonough E, Ayearst R, Eder L, Chandran V, Rosen CF, Thavaneswaran A, Gladman DD. Depression and anxiety in psoriatic disease: prevalence and associated factors. J Rheumatol 2014; 41 (05) 887-96.
    CrossrefPubMedGoogle Scholar
  • 19 Ige OM, Lasebikan VO. Prevalence of depression in tuberculosis patients in comparison with nontuberculosis family contacts visiting the DOTS clinic in a Nigerian tertiary care hospital and its correlation with disease pattern. Ment Health Fam Med 2011; 08 (04) 235-41.
    Google Scholar
  • 20 Loftis JM, Huckans M, Ruimy S, Hinrichs DJ, Hauser P. Depressive symptoms in patients with chronic hepatitis c are correlated with elevated plasma levels of interleukin-1beta and tumor necrosis factor-alpha. Neurosci Lett 2008; 430 (03) 264-8.
    CrossrefPubMedGoogle Scholar
  • 21 Irwin MR. Depression and insomnia in cancer: prevalence, risk factors, and effects on cancer outcomes. Curr Psychiatry Rep 2013; 15 (11) 404.
    CrossrefPubMedGoogle Scholar
  • 22 Ahmad A, Tarhini Gogas H, Kirkwood JM. IFN-a in the treatment of melanoma. J Immunol 2012; 189: 3789-3793.
    CrossrefPubMedGoogle Scholar
  • 23 Rizza P, Moretti F, Belardelli F. Recent advances on the immunomodulatory effects of IFN-alpha: implications for cancer immunotherapy and autoimmunity. Autoimmunity 2010; 43 (03) 204-9.
    CrossrefPubMedGoogle Scholar
  • 24 Dorr RT. Interferon-alpha in malignant and viral diseases. A review. Drugs 1993; 45 (02) 177-211.
    PubMedGoogle Scholar
  • 25 Spennati A, Pariante CM. Withdrawing interferon-a from psychiatric patients: clinical care or unjustifiable stigma?. Psychological Medicine 2013; 43: 1127-1132.
    CrossrefPubMedGoogle Scholar
  • 26 Musselman DL. et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001; 344 (13) 961-6.
    CrossrefPubMedGoogle Scholar
  • 27 Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa, and depression. Hepatology 2000; 31 (06) 1207-11.
    CrossrefPubMedGoogle Scholar
  • 28 Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 2010; 130 (02) 226-38.
    Google Scholar
  • 29 Capuron L, Miller AH. Cytokines and Psychopathology: Lessons from Interferon-alpha. Biol Psychiatry 2004; 56: 819-824.
    CrossrefPubMedGoogle Scholar
  • 30 Schaefer M. et al. Interferon alpha (IFNalpha) and psychiatric syndromes: a review. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2002; 26 (04) 731-46.
    CrossrefPubMedGoogle Scholar
  • 31 Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000; 157 (06) 867-76.
    CrossrefPubMedGoogle Scholar
  • 32 Maes M, Stevens W, DeClerck L, Bridts C, Peeters D, Schotte C, Cosyns P. Immune disorders in depression: higher T helper/T suppressor-cytotoxic cell ratio. Acta Psychiatr Scand 1992; 86 (06) 423-31.
    CrossrefPubMedGoogle Scholar
  • 33 Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H. Increased CD56+ natural killer cells and related cytokines in major depression. Clin Immunol Immunopathol 1996; 78 (01) 83-5.
    CrossrefPubMedGoogle Scholar
  • 34 Müller N, Hofschuster E, Ackenheil M, Mempel W, Eckstein R. Investigations of the cellular immunity during depression and the free interval: evidence for an immune activation in affective psychosis. Prog Neuropsychopharmacol Biol Psychiatry 1993; 17 (05) 713-30.
    CrossrefPubMedGoogle Scholar
  • 35 Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R, Desnyder R. Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995; 34 (04) 301-9.
    CrossrefPubMedGoogle Scholar
  • 36 Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 2005; 88 (02) 167-73.
    CrossrefPubMedGoogle Scholar
  • 37 Kim YK, Suh IB, Kim H, Han CS, Lim CS, Choi SH, Licinio J. The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 2002; 07 (10) 1107-14.
    CrossrefPubMedGoogle Scholar
  • 38 Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. J Clin Psychopharmacol 2001; 21 (02) 199-206.
    CrossrefPubMedGoogle Scholar
  • 39 Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kühn M, Schuld A, Pollmächer T. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 1999; 33 (05) 407-18.
    CrossrefPubMedGoogle Scholar
  • 40 Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67 (05) 446-57.
    CrossrefPubMedGoogle Scholar
  • 41 Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71 (02) 171-86.
    CrossrefPubMedGoogle Scholar
  • 42 Calabrese JR, Skwerer RG, Barna B, Gulledge AD, Valenzuela R, Butkus A, Subichin S, Krupp NE. Depression, immunocompetence, and prostaglandins of the E series. Psychiatry Res 1986; 17 (01) 41-7.
    CrossrefPubMedGoogle Scholar
  • 43 Linnoila M, Whorton AR, Rubinow DR, Cowdry RW, Ninan PT, Waters RN. CSF prostaglandin levels in depressed and schizophrenic patients. Arch Gen Psychiatry 1983; 40 (04) 405-6.
    CrossrefPubMedGoogle Scholar
  • 44 Song C. et al. The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 1998; 49 (03) 211-9.
    CrossrefPubMedGoogle Scholar
  • 45 Müller N. et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006; 11 (07) 680-4.
    CrossrefPubMedGoogle Scholar
  • 46 Abbasi SH, Hosseini F, Modabbernia A, Ashrafi M, Akhondzadeh S. Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord 2012; 141 (2–3): 308-14.
    CrossrefPubMedGoogle Scholar
  • 47 Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, Mohebbi-Rasa S, Raznahan M, Kamalipour A. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 2009; 26 (07) 607-11.
    CrossrefPubMedGoogle Scholar
  • 48 Faridhosseini F, Sadeghi R, Farid L, Pourgholami M. Celecoxib: a new augmentation strategy for depressive mood episodes. A systematic review and meta-analysis of randomized placebo-controlled trials. Hum Psychopharmacol 2014; 29 (03) 216-23.
    CrossrefPubMedGoogle Scholar
  • 49 Fond et al. Effectiveness and tolerance of anti-inflammatory drugs’ add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatr Scand 2014; 129 (03) 163-79.
    CrossrefPubMedGoogle Scholar
  • 50 Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70 (01) 31-41.
    CrossrefPubMedGoogle Scholar
  • 51 Goehler LE, Erisir A, Gaykema RP. Neural-immune interface in the rat area postrema. Neuroscience 2006; 140 (04) 1415-34.
    CrossrefPubMedGoogle Scholar
  • 52 Quan N, Banks WA. Brain–immune communication pathways. Brain, Behavior, and Immunity 2007; 21 (06) 727-35.
    CrossrefPubMedGoogle Scholar
  • 53 Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 1995; 02 (04) 241-8.
    CrossrefPubMedGoogle Scholar
  • 54 Pan W, Banks WA, Kastin AJ. Permeability of the blood-brain and blood-spinal cord barriers to interferons. J Neuroimmunol 1997; 76 (1–2): 105-11.
    CrossrefPubMedGoogle Scholar
  • 55 Banks WA. The blood-brain barrier in psychoneuroimmunology. Immunology and Allergy Clinics of North America 2009; 29 (02) 223-8.
    CrossrefPubMedGoogle Scholar
  • 56 Banks WA, Erickson MA. The blood-brain barrier and immune function and dysfunction. Neurobiology of Disease 2010; 37 (01) 26-32.
    CrossrefPubMedGoogle Scholar
  • 57 Yamada T, Yamanaka I. Microglial localization of alpha-interferon receptor in human brain tissues. Neurosci Lett 1995; 189 (02) 73-6.
    CrossrefPubMedGoogle Scholar
  • 58 Delhaye S, Paul S, Blakqori G, Minet M, Weber F, Staeheli P, Michiels T. Neurons produce type I interferon during viral encephalitis. Proc Natl Acad Sci USA 2006; 103 (20) 7835-40.
    CrossrefPubMedGoogle Scholar
  • 59 Okada K, Kuroda E, Yoshida Y, Yamashita U, Suzumura A, Tsuji S. Effects of interferon-beta on the cytokine production of astrocytes. J Neuroimmunol 2005; 159 (1–2): 48-54.
    CrossrefPubMedGoogle Scholar
  • 60 Makino M, Kitano Y, Komiyama C, Hirohashi M, Kohno M, Moriyama M, Takasuna K. Human interferon-alpha induces immobility in the mouse forced swimming test: involvement of the opioid system. Brain Res 2000; 852 (02) 482-4.
    CrossrefPubMedGoogle Scholar
  • 61 Sammut S, Goodall G, Muscat R. Acute interferonalpha administration modulates sucrose consumption in the rat. Psychoneuroendocrinology 2001; 26 (03) 261-72.
    CrossrefPubMedGoogle Scholar
  • 62 Dafny N. Is interferon-alpha a neuromodulator?. Brain Res Brain Res Rev 1998; 26 (01) 1-15.
    CrossrefPubMedGoogle Scholar
  • 63 Arisi GM. Nervous and immune systems signals and connections: Cytokines in hippocampus physiology and pathology. Epilepsy Behav. 2014 Feb 14; E-Pub ahead of print.
    PubMedGoogle Scholar
  • 64 Deak T. From hippocampus to dorsal horn: the pervasive impact of IL-1 on learning and memory spans the length of the neuroaxis. Brain Behav Immun 2007; 21: 746-7.
    CrossrefPubMedGoogle Scholar
  • 65 Yirmiya R, Goshen I. Immunemodulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011; 25: 181-213.
    CrossrefPubMedGoogle Scholar
  • 66 Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, Thuret S, Price J, Pariante CM. Interleukin-1alpha: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology 2012; 37 (04) 939-49.
    CrossrefPubMedGoogle Scholar
  • 67 Zhang K, Xu H, Cao L, Li K, Huang Q. Interleukin-1alpha inhibits the differentiation of hippocampal neural precursor cells into serotonergic neurons. Brain Res 2013; 1490: 193-201.
    CrossrefPubMedGoogle Scholar
  • 68 Mössner R, Heils A, Stöber G, Okladnova O, Daniel S, Lesch KP. Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6. Neurochem Int 1998; 33 (03) 251-4.
    CrossrefPubMedGoogle Scholar
  • 69 Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 2006; 31 (10) 2121-31.
    CrossrefPubMedGoogle Scholar
  • 70 Tsao CW, Lin YS, Cheng JT, Lin CF, Wu HT, Wu SR, Tsai WH. Interferon-alpha-induced serotonin uptake in Jurkat T cells via mitogen-activated protein kinase and transcriptional regulation of the serotonin transporter. J Psychopharmacol 2008; 22 (07) 753-60.
    CrossrefPubMedGoogle Scholar
  • 71 Linthorst AC, Flachskamm C, Müller-Preuss P, Holsboer F, Reul JM. Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J Neurosci 1995; 15 (04) 2920-34.
    CrossrefPubMedGoogle Scholar
  • 72 Merali Z, Lacosta S, Anisman H. Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study. Brain Res 1997; 761 (02) 225-35.
    CrossrefPubMedGoogle Scholar
  • 73 Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH. Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res 1994; 643 (1–2): 40-9.
    CrossrefPubMedGoogle Scholar
  • 74 Song C, Merali Z, Anisman H. Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 1999; 88 (03) 823-36.
    CrossrefPubMedGoogle Scholar
  • 75 Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an 1. integrated view of depression. Mol Psychiatry 2007; 12 (11) 988-1000.
    CrossrefPubMedGoogle Scholar
  • 76 Gideons ES, Kavalali ET, Monteggia LM. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci USA 2014; 111 (23) 8649-54.
    CrossrefPubMedGoogle Scholar
  • 77 Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007; 21 (01) 9-19.
    CrossrefPubMedGoogle Scholar
  • 78 Jeannin P, Jaillon S, Delneste Y. Pattern recognition receptors in the immune response against dying cells. Curr Opin Immunol 2008; 20 (05) 530-7.
    CrossrefPubMedGoogle Scholar
  • 79 Ginhoux F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330 (6005): 841-5.
    CrossrefPubMedGoogle Scholar
  • 80 Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 2009; 29 (13) 3974-80.
    CrossrefPubMedGoogle Scholar
  • 81 Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007; 10 (11) 1387-94.
    CrossrefPubMedGoogle Scholar
  • 82 Koning N, Uitdehaag BM, Huitinga I, Hoek RM. Restoring immune suppression in the multiple sclerosis brain. Prog Neurobiol 2009; 89 (04) 359-68.
    CrossrefPubMedGoogle Scholar
  • 83 Mantovani A. From phagocyte diversity and activation to probiotics: back to Metchnikoff. Eur J Immunol 2008; 38 (12) 3269-73.
    CrossrefPubMedGoogle Scholar
  • 84 Kim HJ, Ifergan I, Antel JP, Seguin R, Duddy M, Lapierre Y, Jalili F, Bar-Or A. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 2004; 172 (11) 7144-53.
    CrossrefPubMedGoogle Scholar
  • 85 Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 2006; 31 (01) 149-60.
    CrossrefPubMedGoogle Scholar
  • 86 Butovsky O. et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 2006; 116 (04) 905-15.
    CrossrefPubMedGoogle Scholar
  • 87 Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron 2013; 77 (01) 10-8.
    CrossrefPubMedGoogle Scholar
  • 88 Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308 (5726): 1314-8.
    CrossrefPubMedGoogle Scholar
  • 89 Hoek RM. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 2000; 290 5497 1768-71.
    CrossrefPubMedGoogle Scholar
  • 90 Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, Barclay AN. Lymphoid/ neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 2000; 13 (02) 233-42.
    CrossrefPubMedGoogle Scholar
  • 91 Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J Neuroinflammation 2011; 08: 9.
    CrossrefPubMedGoogle Scholar
  • 92 Cardona AE. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006; 09 (07) 917-24.
    CrossrefPubMedGoogle Scholar
  • 93 Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 2007; 30 (10) 527-35.
    CrossrefPubMedGoogle Scholar
  • 94 Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke HW, Kettenmann H. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun 2012; 26 (03) 419-28.
    CrossrefPubMedGoogle Scholar
  • 95 Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 2012; 26 (03) 469-79.
    CrossrefPubMedGoogle Scholar
  • 96 Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A. Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology 2011; 61 (04) 592-9.
    CrossrefPubMedGoogle Scholar
  • 97 Horikawa H, Kato TA, Mizoguchi Y, Monji A, Seki Y, Ohkuri T, Gotoh L, Yonaha M, Ueda T, Hashioka S, Kanba S. Inhibitory effects of SSRIs on IFNalpha induced microglial activation through the regulation of intracellular calcium. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34 (07) 1306-16.
    CrossrefPubMedGoogle Scholar
  • 98 Hashioka S, Klegeris A, Monji A, Kato T, Sawada M, McGeer PL, Kanba S. Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol 2007; 206 (01) 33-42.
    CrossrefPubMedGoogle Scholar
  • 99 Obuchowicz E, Kowalski J, Labuzek K, Krysiak R, Pendzich J, Herman ZS. Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures. Int J Neuropsychopharmacol 2006; 09 (01) 27-35.
    Google Scholar
  • 100 Pitossi F, del Rey A, Kabiersch A, Besedovsky H. Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice. J Neurosci Res 1997; 48 (04) 287-98.
    CrossrefPubMedGoogle Scholar
  • 101 Di Filippo M. et al. Effects of central and peripheral inflammation on hippocampal synaptic plasticity. Neurobiol Dis 2013; 52: 229-36.
    CrossrefPubMedGoogle Scholar
  • 102 Yang TT, Lin C, Hsu CT, Wang TF, Ke FY, Kuo YM. Differential distribution and activation of microglia in the brain of male C57BL/6J mice. Brain Struct Funct 2013; 218 (04) 1051-60.
    CrossrefPubMedGoogle Scholar
  • 103 Machado A. et al. Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson’s disease incidence. Parkinsons Dis 2011; 2011: 393769.
    PubMedGoogle Scholar
  • 104 D’Mello C, Le T Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci 2009; 29 (07) 2089-102.
    CrossrefPubMedGoogle Scholar
  • 105 O’Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 2009; 14 (05) 511-22.
    CrossrefPubMedGoogle Scholar
  • 106 Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 2008; 05: 15.
    CrossrefPubMedGoogle Scholar
  • 107 Molina-Hernández M, Tellez-Alcántara NP, Pérez-García J, Olivera-Lopez JI, Jaramillo-Jaimes MT. Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32 (02) 380-6.
    CrossrefPubMedGoogle Scholar
  • 108 Corona AW, Huang Y, O’Connor JC, Dantzer R, Kelley KW, Popovich PG, Godbout JP. Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide. J Neuroinflammation 2010; 07: 93.
    CrossrefPubMedGoogle Scholar
  • 109 Frick LR, Williams K, Pittenger C. Microglial dysregulation in psychiatric disease. Clin Dev Immunol 2013; 2013: 608-654.
    Google Scholar
  • 110 Hinwood M, Morandini J, Day TA, Walker FR. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex 2012; 22 (06) 1442-54.
    CrossrefPubMedGoogle Scholar
  • 111 Tynan RJ, Naicker S, Hinwood M, Nalivaiko E, Buller KM, Pow DV, Day TA, Walker FR. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun 2010; 24 (07) 1058-68.
    CrossrefPubMedGoogle Scholar
  • 112 Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, Nelson RJ, Godbout JP, Sheridan JF. Alpha-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 2011; 31 (17) 6277-88.
    CrossrefPubMedGoogle Scholar
  • 113 Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 2007; 21 (01) 47-59.
    CrossrefPubMedGoogle Scholar
  • 114 Arakawa S, Shirayama Y, Fujita Y, Ishima T, Horio M, Muneoka K, Iyo M, Hashimoto K. Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline. Pharmacol Biochem Behav 2012; 100 (03) 601-6.
    CrossrefPubMedGoogle Scholar
  • 115 Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11 (10) 889-96.
    CrossrefPubMedGoogle Scholar
  • 116 Bowdish DM, Loffredo MS, Mukhopadhyay S, Mantovani A, Gordon S. Macrophage receptors implicated in the “adaptive” form of innate immunity. Microbes Infect 2007; 09 (14–15): 1680-7.
    CrossrefPubMedGoogle Scholar
  • 117 Frank MG, Miguel ZD, Watkins LR, Maier SF. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun 2010; 24 (01) 19-30.
    CrossrefPubMedGoogle Scholar
  • 118 Stark JL, Avitsur R, Padgett DA, Campbell KA, Beck FM, Sheridan JF. Social stress induces glucocorticoid resistance in macrophages. Am J Physiol Regul Integr Comp Physiol 2001; 280 (06) R1799-805.
    CrossrefPubMedGoogle Scholar
  • 119 Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014 May 20. pii: S0889-1591(14)00129–9
    PubMedGoogle Scholar
  • 120 Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 2008; 42 (02) 151-7.
    CrossrefPubMedGoogle Scholar
  • 121 Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, Lee SC. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 2009; 35 (03) 306-28.
    CrossrefPubMedGoogle Scholar
  • 122 Hannestad J. et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a (11C)PBR28 PET study. Brain Behav Immun 2013; 33: 131-8.
    CrossrefPubMedGoogle Scholar
  • 123 de Vries EF, Dierckx RA, Klein HC. Nuclear imaging of inflammation in neurologic and psychiatric disorders. Curr Clin Pharmacol 2006; 01 (03) 229-42.
    CrossrefPubMedGoogle Scholar
  • 124 Kempton MJ, Salvador Z, Munafò MR, Geddes JR, Simmons A, Frangou S, Williams SC. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 2011; 68 (07) 675-90.
    CrossrefPubMedGoogle Scholar
  • 125 McKinnon MC, Yucel K, Nazarov A, MacQueen GM. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. J Psychiatry Neurosci 2009; 34 (01) 41-54.
    PubMedGoogle Scholar
  • 126 Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 2003; 54 (03) 338-52.
    CrossrefPubMedGoogle Scholar
  • 127 WHO. Global burden of diesease study. 2001
    PubMed
  • 128 Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion VSileni. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev 2013; 18 6: CD008955.
    Google Scholar