Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)—MBP87–99[A91, A96], MBP87–99[A91], and MBP87–99[R91, A96]—in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87–99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87–99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87–99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87–99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87–99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune–neural interactions may impact central nervous system function and alter an individual’s response to stress.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Martinowich K, Jimenez DV, Zarate CA Jr., Manji HK. Rapid antidepressant effects: moving right along. Mol Psychiatry. 2013;18:856–63.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.
Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nat Neurosci. 2015;18:1386–93.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.
Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21:1696–709.
Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005;88:167–73.
Sutcigil L, Oktenli C, Musabak U, Bozkurt A, Cansever A, Uzun O, et al. Pro- and anti-inflammatory cytokine balance in major depression: effect of sertraline therapy. Clin Dev Immunol. 2007;2007:76396.
Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet. 2002;360:1831–7.
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.
Felger JC, Li Z, Haroon E, Woolwine BJ, Jung MY, Hu X, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21:1358–65.
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009;66:407–14.
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;9:46–56.
D’Mello C, Swain MG. Immune-to-brain communication pathways in inflammation-associated sickness and depression. Curr Top Behav Neurosci. 2017;31:73–94.
Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci USA. 2011;108:9262–7.
Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M, et al. Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology. 2001;24:531–44.
Alboni S, Benatti C, Montanari C, Tascedda F, Brunello N. Chronic antidepressant treatments resulted in altered expression of genes involved in inflammation in the rat hypothalamus. Eur J Pharm. 2013;721:158–67.
Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622–30.
Brachman RA, Lehmann ML, Maric D, Herkenham M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530–8.
Katsara M, Deraos G, Tselios T, Matsoukas MT, Friligou I, Matsoukas J, et al. Design and synthesis of a cyclic double mutant peptide (cyclo(87-99)[A91,A96]MBP87-99) induces altered responses in mice after conjugation to mannan: implications in the immunotherapy of multiple sclerosis. J Med Chem. 2009;52:214–8.
Karin N, Mitchell DJ, Brocke S, Ling N, Steinman L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J Exp Med. 1994;180:2227–37.
Tselios T, Apostolopoulos V, Daliani I, Deraos S, Grdadolnik S, Mavromoustakos T, et al. Antagonistic effects of human cyclic MBP(87-99) altered peptide ligands in experimental allergic encephalomyelitis and human T-cell proliferation. J Med Chem. 2002;45:275–83.
Gaur A, Boehme SA, Chalmers D, Crowe PD, Pahuja A, Ling N, et al. Amelioration of relapsing experimental autoimmune encephalomyelitis with altered myelin basic protein peptides involves different cellular mechanisms. J Neuroimmunol. 1997;74:149–58.
Smilek DE, Wraith DC, Hodgkinson S, Dwivedy S, Steinman L, McDevitt HO. A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 1991;88:9633–7.
Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I, et al. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest. 2001;108:591–9.
Lewitus GM, Wilf-Yarkoni A, Ziv Y, Shabat-Simon M, Gersner R, Zangen A, et al. Vaccination as a novel approach for treating depressive behavior. Biol Psychiatry. 2009;65:283–8.
Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P. p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci. 2013;14:673–80.
Svenningsson P, Greengard P. p11 (S100A10)–an inducible adaptor protein that modulates neuronal functions. Curr Opin Pharm. 2007;7:27–32.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80.
Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N. Identification of the cortical neurons that mediate antidepressant responses. Cell. 2012;149:1152–63.
Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Lievano M, Ghose S, et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med. 2010;2:54ra76.
Seo JS, Wei J, Qin L, Kim Y, Yan Z, Greengard P. Cellular and molecular basis for stress-induced depression. Mol Psychiatry. 2017;22:1440–7.
Zhu WL, Wang SJ, Liu MM, Shi HS, Zhang RX, Liu JF, et al. Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci. 2013;38:306–16.
Sukoff Rizzo SJ, Neal SJ, Hughes ZA, Beyna M, Rosenzweig-Lipson S, Moss SJ, et al. Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes. Transl Psychiatry. 2012;2:e199.
Chen Y, Chen J, Wen H, Gao P, Wang J, Zheng Z, et al. S100A10 downregulation inhibits the phagocytosis of Cryptococcus neoformans by murine brain microvascular endothelial cells. Micro Pathog. 2011;51:96–100.
Jian M, Luo YX, Xue YX, Han Y, Shi HS, Liu JF, et al. eIF2alpha dephosphorylation in basolateral amygdala mediates reconsolidation of drug memory. J Neurosci. 2014;34:10010–21.
Li SX, Han Y, Xu LZ, Yuan K, Zhang RX, Sun CY, et al. Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Mol Psychiatry. 2018;23:597–608.
Suo L, Zhao L, Si J, Liu J, Zhu W, Chai B, et al. Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology. 2013;38:1387–1400.
Shi HS, Zhu WL, Liu JF, Luo YX, Si JJ, Wang SJ, et al. PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3. Neuropsychopharmacology. 2012;37:2671–83.
Okamoto H, Voleti B, Banasr M, Sarhan M, Duric V, Girgenti MJ, et al. Wnt2 expression and signaling is increased by different classes of antidepressant treatments. Biol Psychiatry. 2010;68:521–7.
Han Y, Luo Y, Sun J, Ding Z, Liu J, Yan W, et al. AMPK signaling in the dorsal hippocampus negatively regulates contextual fear memory formation. Neuropsychopharmacology. 2016;41:1849–64.
Xue YX, Chen YY, Zhang LB, Zhang LQ, Huang GD, Sun SC, et al. Selective inhibition of amygdala neuronal ensembles encoding nicotine-associated memories inhibits nicotine preference and relapse. Biol Psychiatry. 2017;82:781–93.
Kafetzopoulos V, Kokras N, Sotiropoulos I, Oliveira JF, Leite-Almeida H, Vasalou A, et al. The nucleus reuniens: a key node in the neurocircuitry of stress and depression. Mol Psychiatry. 2018;23:579–86.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.
Engler H, Brendt P, Wischermann J, Wegner A, Rohling R, Schoemberg T, et al. Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms. Mol Psychiatry. 2017;22:1448–54.
Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry. 2008;13:717–28.
Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol. 2009;40:139–56.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.
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;162:175–7.
Levine J, Barak Y, Chengappa KN, Rapoport A, Rebey M, Barak V. Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology. 1999;40:171–6.
Alesci S, Martinez PE, Kelkar S, Ilias I, Ronsaville DS, Listwak SJ, et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab. 2005;90:2522–30.
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41.
Wood SK, Wood CS, Lombard CM, Lee CS, Zhang XY, Finnell JE, et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats. Biol Psychiatry. 2015;78:38–48.
Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13:1173–5.
Slyepchenko A, Maes M, Kohler CA, Anderson G, Quevedo J, Alves GS, et al. T helper 17 cells may drive neuroprogression in major depressive disorder: proposal of an integrative model. Neurosci Biobehav Rev. 2016;64:83–100.
Katsara M, Yuriev E, Ramsland PA, Tselios T, Deraos G, Lourbopoulos A, et al. Altered peptide ligands of myelin basic protein (MBP87-99) conjugated to reduced mannan modulate immune responses in mice. Immunology. 2009;128:521–33.
Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA. 2008;105:751–6.
Goshen I, Yirmiya R. Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocr. 2009;30:30–45.
Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961–6.
Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–52.
Brymer KJ, Romay-Tallon R, Allen J, Caruncho HJ, Kalynchuk LE. Exploring the potential antidepressant mechanisms of TNFalpha antagonists. Front Neurosci. 2019;13:98.
Riga MS, Teruel-Marti V, Sanchez C, Celada P, Artigas F. Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex. Neuropharmacology. 2017;113:148–55.
Wu PR, Cho KK, Vogt D, Sohal VS, Rubenstein JL. The cytokine CXCL12 promotes basket interneuron inhibitory synapses in the medial prefrontal cortex. Cereb Cortex. 2017;27:4303–13.
Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell. 1989;59:247–55.
Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA. 2015;112:12468–73.
McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23:1421–31.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497–511.
Pearson-Leary J, Zhao C, Bittinger K, Eacret D, Luz S, Vigderman AS, et al. The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry 2019; https://doi.org/10.1038/s41380-019-0380-x. [Epub ahead of print]
Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J, et al. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry. 2016;21:797–805.
Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Transl Psychiatry. 2017;7:e1138.
Weiss R, Bitton A, Ben Shimon M, Elhaik Goldman S, Nahary L, Cooper I, et al. Annexin A2, autoimmunity, anxiety and depression. J Autoimmun. 2016;73:92–99.
Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P. Neurogenic effects of fluoxetine are attenuated inp11 (S100A10) knockout mice. Biol Psychiatry. 2010;67:1048–56.
Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5.
Lee KW, Westin L, Kim J, Chang JC, Oh YS, Amreen B, et al. Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol Psychiatry. 2015;20:1546–56.
Warner-Schmidt JL, Flajolet M, Maller A, Chen EY, Qi H, Svenningsson P, et al. Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. J Neurosci. 2009;29:1937–46.
Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006;31:2121–31.
Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010;35:2510–20.
Linthorst AC, Flachskamm C, Muller-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;15:2920–34.
Zhang J, Terreni L, De Simoni MG, Dunn AJ. Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. Neurochem Int. 2001;38:303–8.
Baganz NL, Lindler KM, Zhu CB, Smith JT, Robson MJ, Iwamoto H, et al. A requirement of serotonergic p38alpha mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors. Transl Psychiatry. 2015;5:e671.
Huang XL, Pawliczak R, Yao XL, Cowan MJ, Gladwin MT, Walter MJ, et al. Interferon-gamma induces p11 gene and protein expression in human epithelial cells through interferon-gamma-activated sequences in the p11 promoter. J Biol Chem. 2003;278:9298–308.
Guo J, Zhang W, Zhang L, Ding H, Zhang J, Song C, et al. Probable involvement of p11 with interferon alpha induced depression. Sci Rep. 2016;6:17029.
Jansen R, Penninx BW, Madar V, Xia K, Milaneschi Y, Hottenga JJ, et al. Gene expression in major depressive disorder. Mol Psychiatry. 2016;21:339–47.
Svenningsson P, Berg L, Matthews D, Ionescu DF, Richards EM, Niciu MJ, et al. Preliminary evidence that early reduction in p11 levels in natural killer cells and monocytes predicts the likelihood of antidepressant response to chronic citalopram. Mol Psychiatry. 2014;19:962–4.
Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P, et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry. 2010;68:528–35.
Park SW, Nhu le H, Cho HY, Seo MK, Lee CH, Ly NN, et al. p11 mediates the BDNF-protective effects in dendritic outgrowth and spine formation in B27-deprived primary hippocampal cells. J Affect Disord. 2016;196:1–10.
Werneburg S, Feinberg PA, Johnson KM, Schafer DP. A microglia-cytokine axis to modulate synaptic connectivity and function. Curr Opin Neurobiol. 2017;47:138–45.
This work was supported in part by the National Natural Science Foundation of China (Nos. 81701312, 81871046, 81722018, and 81521063), National Basic Research Program of China (Nos. 2015CB856400, 2015CB559200, and 2015CB553503), Funds for Excellent PhD Graduates of Peking University Health Science Center (No. BMU20160569), the interdisciplinary medicine Seed Fund of Peking University (Nos. BMU2017MX022 and BMU2018MX024), and Beijing Brain Project (No. Z171100000117014).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Han, Y., Sun, CY., Meng, SQ. et al. Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects. Mol Psychiatry 25, 1260–1274 (2020). https://doi.org/10.1038/s41380-019-0470-9
This article is cited by
Neurocan regulates vulnerability to stress and the anti-depressant effect of ketamine in adolescent rats
Molecular Psychiatry (2022)
Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression
Molecular Psychiatry (2021)
Gut microbiota modulates the inflammatory response and cognitive impairment induced by sleep deprivation
Molecular Psychiatry (2021)
Molecular Psychiatry, August 2020: new impact factor, and highlights of recent advances in psychiatry, including an overview of the brain’s response to stress during infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Molecular Psychiatry (2020)
Advances in depression research: second special issue, 2020, with highlights on biological mechanisms, clinical features, co-morbidity, genetics, imaging, and treatment
Molecular Psychiatry (2020)