Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice

Journal of Neuroinflammation

Lena Brundin⁴  Tomas Deierborg⁶  Jack Lipton⁷  Richard Bucala²  Analise Sauro¹  Shorena Janelidze³  Cecilie Bay-Richter⁵ 

[1] Department of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA;Department of Medicine, Yale School of Medicine, New Haven, CT, USA;Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden;Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, USA;Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark;Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, BMC, Lund University, Lund, Sweden;Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA

关键词: Inflammation;    Dopamine;    Cytokines;    Depression;    Macrophage migration inhibitory factor;   

Others  :  1227064
DOI  :  10.1186/s12974-015-0387-4

 received in 2015-03-22, accepted in 2015-08-24,  发布年份 2015

【 摘 要 】

Background

Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome.

Methods

MIF KO and WT mice were tested for spontaneous locomotor activity in the open-field test, anhedonia-like behaviour in the sucrose preference test (SPT), as well as behavioural despair in the forced swim test (FST) and tail suspension test (TST). Brain and serum levels of cytokines, the enzymes COX-2 and indoleamine-2,3-dioxygenase (IDO) and the glucocorticoid hormone corticosterone were measured by RT-qPCR and/or high-sensitivity electrochemiluminescence-based multiplex immunoassays. Monoamines and metabolites were examined using HPLC.

Results

We found that MIF KO mice of both sexes displayed decreased depressive-like behaviour as measured in the FST. In the TST, a similar, but non-significant, trend was also found. IFN-γ levels were decreased, and dopamine metabolism increased in MIF KO mice. Decreased brain IFN-γ levels predicted higher striatal dopamine levels, and high dopamine levels in turn were associated with reduced depressive-like behaviour. In the SPT, there was a sex-specific discrepancy, where male MIF KO mice showed reduced anhedonia-like behaviour whereas female KO mice displayed increased anhedonia-like behaviour. Our results suggest that this relates to the increased corticosterone levels detected in female, but not male, MIF KO mice.

Conclusions

Our findings support that MIF is involved in the generation of depressive-like symptoms, potentially by the effects of IFN-γ on dopamine metabolism. Our data further suggests a sex-specific regulation of the involved mechanisms.

【 授权许可】

   
2015 Bay-Richter et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

Fig. 8.

Fig. 9.

【 参考文献 】

• [1]Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, et al.: Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996, 276(4):293-9.
• [2]Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W, Hirschfeld RM, et al.: Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992, 49(10):809-16.
• [3]Williams JM, Russell IT, Crane C, Russell D, Whitaker CJ, Duggan DS, et al.: Staying well after depression: trial design and protocol. BMC Psychiatry 2010, 10(1):23. BioMed Central Full Text
• [4]Capuron L, Fornwalt FB, Knight BT, Harvey PD, Ninan PT, Miller AH: Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord 2009, 119(1-3):181.
• [5]Capuron L, Ravaud A, Dantzer R: Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy. J Clin Oncol 2000, 18(10):2143-51.
• [6]Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ, et al.: Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry 2009, 65(4):296-303.
• [7]Raison CL, Demetrashvili M, Capuron L, Miller AH: Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 2005, 19(2):105-23.
• [8]Bay-Richter C, Janelidze S, Hallberg L, Brundin L: Changes in behaviour and cytokine expression upon a peripheral immune challenge. Behav Brain Res 2011, 222(1):193-9.
• [9]Dunn AJ, Swiergiel AH, de Beaurepaire R: Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev 2005, 29(4-5):891-909.
• [10]Yirmiya R: Endotoxin produces a depressive-like episode in rats. Brain Res 1996, 711(1-2):163-74.
• [11]Connor TJ, Leonard BE: Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci 1998, 62(7):583-606.
• [12]Hestad KA, Tonseth S, Stoen CD, Ueland T, Aukrust P: Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J ECT 2003, 19(4):183-8.
• [13]Thomas AJ, Davis S, Morris C, Jackson E, Harrison R, O’Brien JT: Increase in interleukin-1beta in late-life depression. Am J Psychiatry 2005, 162(1):175-7.
• [14]Müller N, Schwarz MJ, Dehning S, Douche A, Cerovecki A, Goldstein-Müller B, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M: 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(7):680-4.
• [15]Bloom J, Al-Abed Y: MIF: mood improving/inhibiting factor? J Neuroinflammation 2014, 11:11. BioMed Central Full Text
• [16]Ohkawara T, Takeda H, Miyashita K, Nishiwaki M, Nakayama T, Taniguchi M, et al.: Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor. Histochem Cell Biol 2006, 125(5):575-82.
• [17]Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, et al.: Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with Gram-negative bacteremia in older adults. J Infect Dis 2014, 209(5):764-8.
• [18]Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A: Up-regulation of cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells by macrophage migration inhibitory factor: involvement of novel kinase signaling pathways. Endocrinology 2009, 150(7):3128-37.
• [19]Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, et al.: MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995, 377(6544):68-71.
• [20]Fingerle-Rowson G, Koch P, Bikoff R, Lin X, Metz CN, Dhabhar FS, et al.: Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo. Am J Pathol 2003, 162(1):47-56.
• [21]Mitchell RA, Metz CN, Peng T, Bucala R: Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J Biol Chem 1999, 274(25):18100-6.
• [22]Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J: Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 2002, 4(4):449-60.
• [23]Bucala R: Signal transduction. A most interesting factor. Nature 2000, 408(6809):146-7.
• [24]Cvetkovic I, Al-Abed Y, Miljkovic D, Maksimovic-Ivanic D, Roth J, Bacher M, et al.: Critical role of macrophage migration inhibitory factor activity in experimental autoimmune diabetes. Endocrinology 2005, 146(7):2942-51.
• [25]Musil R, Schwarz MJ, Riedel M, Dehning S, Cerovecki A, Spellmann I, et al.: Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression—no influence of celecoxib treatment. J Affect Disord 2011, 134(1-3):217-25.
• [26]Edwards KM, Bosch JA, Engeland CG, Cacioppo JT, Marucha PT: Elevated macrophage migration inhibitory factor (MIF) is associated with depressive symptoms, blunted cortisol reactivity to acute stress, and lowered morning cortisol. Brain Behav Immun 2010, 24(7):1202-8.
• [27]Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, et al.: Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology 2012, 38:377-85.
• [28]Lu XT, Liu YF, Zhao L, Li WJ, Yang RX, Yan FF, et al.: Chronic psychological stress induces vascular inflammation in rabbits. Stress. 2012, 16:87-98.
• [29]Conboy L, Varea E, Castro JE, Sakouhi-Ouertatani H, Calandra T, Lashuel HA, et al.: Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors. Mol Psychiatry 2011, 16(5):533-47.
• [30]Moon HY, Kim SH, Yang YR, Song P, Yu HS, Park HG, et al.: Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise. Proc Natl Acad Sci U S A 2012, 109(32):13094-9.
• [31]Willner P: Behavioural models in psychopharmacology: theoretical, industrial, and clinical perspectives. Cambridge University Press, UK; 1991.
• [32]Porsolt RD, Le Pichon M, Jalfre M: Depression: a new animal model sensitive to antidepressant treatments. Nature 1977, 266(5604):730-2.
• [33]Yan HC, Cao X, Das M, Zhu XH, Gao TM: Behavioral animal models of depression. Neurosci Bull 2010, 26(4):327-37.
• [34]Papp M, Willner P, Muscat R: An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology (Berl) 1991, 104(2):255-9.
• [35]Inacio AR, Ruscher K, Leng L, Bucala R, Deierborg T: Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke. J Cereb Blood Flow Metab 2011, 31(4):1093-106.
• [36]Petit-Demouliere B, Chenu F, Bourin M: Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl) 2005, 177(3):245-55.
• [37]Steru L, Chermat R, Thierry B, Simon P: The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985, 85(3):367-70.
• [38]Cryan JF, Mombereau C, Vassout A: The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 2005, 29(4-5):571-625.
• [39]Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001, 29(9):e45.
• [40]McNamara RK, Sullivan J, Richtand NM, Jandacek R, Rider T, Tso P, et al.: Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult DBA/2J mice: relationship with ventral striatum dopamine concentrations. Synapse 2008, 62(10):725-35.
• [41]Christian LM, Franco A, Iams JD, Sheridan J, Glaser R: Depressive symptoms predict exaggerated inflammatory responses to an in vivo immune challenge among pregnant women. Brain Behav Immun 2010, 24(1):49-53.
• [42]Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, et al.: Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology 2013, 38(3):377-85.
• [43]Katsuura S, Kamezaki Y, Yamagishi N, Kuwano Y, Nishida K, Masuda K, et al.: Circulating vascular endothelial growth factor is independently and negatively associated with trait anxiety and depressive mood in healthy Japanese university students. Int J Psychophysiol 2011, 81(1):38-43.
• [44]Owens M, Herbert J, Jones PB, Sahakian BJ, Wilkinson PO, Dunn VJ, et al.: Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms. Proc Natl Acad Sci U S A 2014, 111(9):3638-43.
• [45]Silverman MN, Sternberg EM: Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci 2012, 1261:55-63.
• [46]Stokes PE: The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression. Eur Neuropsychopharmacol 1995, 5(1):77-82.
• [47]Halbreich U, Lumley LA: The multiple interactional biological processes that might lead to depression and gender differences in its appearance. J Affect Disord 1993, 29(2-3):159-73.
• [48]Bucala R: MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response. FASEB J 1996, 10(14):1607-13.
• [49]Garner JP: Stereotypies and other abnormal repetitive behaviors: potential impact on validity, reliability, and replicability of scientific outcomes. ILAR J 2005, 46(2):106-17.
• [50]Clayton JA, Collins FS: Policy: NIH to balance sex in cell and animal studies. Nature 2014, 509(7500):282-3.
• [51]Turtzo LC, Li J, Persky R, Benashski S, Weston G, Bucala R, et al.: Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice. Neurobiol Dis 2013, 54:421-31.
• [52]DeVries AC, Joh HD, Bernard O, Hattori K, Hurn PD, Traystman RJ, Alkayed NJ: Social stress exacerbates stroke outcome by suppressing Bcl-2 expression. Proc Natl Acad Sci U S A 2001, 98(20):11824-8.
• [53]Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW: From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008, 9(1):46-56.
• [54]Fragoso YD, Frota ER, Lopes JS, Noal JS, Giacomo MC, Gomes S, Gonçalves MV, da Gama PD, Finkelsztejn A: Severe depression, suicide attempts, and ideation during the use of interferon beta by patients with multiple sclerosis. Clin Neuropharmacol 2010, 33(6):312-6.
• [55]Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, et al.: Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 2011, 16(7):751-62.
• [56]Oxenkrug G, Perianayagam M, Mikolich D, Requintina P, Shick L, Ruthazer R, et al.: Interferon-gamma (+874) T/A genotypes and risk of IFN-alpha-induced depression. J Neural Transm 2011, 118(2):271-4.
• [57]O’connor JC, Andre C, Wang YX, Lawson MA, Szegedi SS, Lestage J, et al.: Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to Bacillus Calmette-Guerin. J Neurosci 2009, 29(13):4200-9.
• [58]Sperner-Unterweger B, Kohl C, Fuchs D: Immune changes and neurotransmitters: possible interactions in depression? Prog Neuropsychopharmacol Biol Psychiatry 2012, 48:268-76.
• [59]Nestler EJ, Carlezon WA Jr: The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006, 59(12):1151-9.
• [60]Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, et al.: Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006, 311:864-8.
• [61]Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Kumar A, Eisch AJ, Self DW, Lee FS, Tamminga CA, Cooper DC, Gershenfeld HK, Nestler EJ: Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007, 131(2):391-404.