Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway

Abstract

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: IFNAR antibody treatment attenuates chronic stress-induced deficits in social behavior and spatial working memory.
Fig. 2: IFNAR antibody treatment attenuates chronic stress-induced infiltration of macrophages and increases in IFN-I-stimulated gene in the PFC.
Fig. 3: IFNAR antibody treatment attenuates chronic stress-induced changes in serum inflammatory markers, and in M1 and M2 markers in the PFC.
Fig. 4: Complement component 3 mediates IFNβ–induced neuroinflammation and deficits in social behavior.
Fig. 5: Increased expression of IFI44 and Mx1 in the PFC of depressed subjects.

Similar content being viewed by others

References

  1. Marshall PS, Watson D, Steinberg P, Cornblatt B, Peterson PK, Callies A, et al. An assessment of cognitive function and mood in chronic fatigue syndrome. Biol Psychiatry. 1996;39:199–206.

    Article  CAS  PubMed  Google Scholar 

  2. Beck AT. Depression: clinical, experimental, and theoretical aspects.1967.

  3. Enns MW, Bernstein CN, Kroeker K, Graff L, Walker JR, Lix LM, et al. The association of fatigue, pain, depression and anxiety with work and activity impairment in immune mediated inflammatory diseases. PLoS One. 2018;13:e0198975.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Feinstein A, Brochet B, Sumowski J. The cognitive effects of anxiety and depression in immune-mediated inflammatory diseases. Neurology. 2019;92:211–2.

  5. Whitehouse CE, Fisk JD, Bernstein CN, Berrigan LI, Bolton JM, Graff LA, et al. Comorbid anxiety, depression, and cognition in MS and other immune-mediated disorders. Neurology. 2019;92:e406–17.

  6. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140:774–815.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Schedlowski M, Engler H, Grigoleit JS. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun. 2014;35:1–8.

    Article  CAS  PubMed  Google Scholar 

  8. Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–63.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008;63:1022–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Corona AW, Fenn AM, Godbout JP. Cognitive and behavioral consequences of impaired immunoregulation in aging. J Neuroimmune Pharm. 2012;7:7–23.

    Article  Google Scholar 

  11. Munhoz CD, Lepsch LB, Kawamoto EM, Malta MB, Lima Lde S, Avellar MC, et al. Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci. 2006;26:3813–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Crider A, Feng T, Pandya CD, Davis T, Nair A, Ahmed AO, et al. Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior. Brain Behav Immun. 2018;70:246–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pyter LM, Kelly SD, Harrell CS, Neigh GN. Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats. Brain Behav Immun. 2013;30:88–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, et al. beta-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci. 2011;31:6277–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry. 2014;19:699–709.

    Article  CAS  PubMed  Google Scholar 

  16. McKim DB, Patterson JM, Wohleb ES, Jarrett BL, Reader BF, Godbout JP, et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol Psychiatry. 2016;79:803–13.

    Article  CAS  PubMed  Google Scholar 

  17. Wohleb ES, Patterson JM, Sharma V, Quan N, Godbout JP, Sheridan JF. Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior. J Neurosci. 2014;34:2583–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schreiber G, Piehler J. The molecular basis for functional plasticity in type I interferon signaling. Trends Immunol. 2015;36:139–49.

    Article  CAS  PubMed  Google Scholar 

  19. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7:131–7.

    Article  CAS  PubMed  Google Scholar 

  20. de Weerd NA, Samarajiwa SA, Hertzog PJ. Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 2007;282:20053–7.

    Article  PubMed  CAS  Google Scholar 

  21. Blank T, Prinz M. Type I interferon pathway in CNS homeostasis and neurological disorders. Glia. 2017;65:1397–406.

    Article  PubMed  Google Scholar 

  22. Mendoza-Fernandez V, Andrew RD, Barajas-Lopez C. Interferon-alpha inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus. Brain Res. 2000;885:14–24.

    Article  CAS  PubMed  Google Scholar 

  23. Schrott LM, Crnic LS. Increased anxiety behaviors in autoimmune mice. Behav Neurosci. 1996;110:492–502.

    Article  CAS  PubMed  Google Scholar 

  24. Prinz M, Knobeloch KP. Type I interferons as ambiguous modulators of chronic inflammation in the central nervous system. Front Immunol. 2012;3:67.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vattakatuchery JJ, Rickards H, Cavanna AE. Pathogenic mechanisms of depression in multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2011;23:261–76.

    Article  CAS  PubMed  Google Scholar 

  26. Dowell NG, Cooper EA, Tibble J, Voon V, Critchley HD, Cercignani M, et al. Acute changes in striatal microstructure predict the development of interferon-alpha induced fatigue. Biol Psychiatry. 2016;79:320–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McNutt MD, Liu S, Manatunga A, Royster EB, Raison CL, Woolwine BJ, et al. Neurobehavioral effects of interferon-alpha in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology 2012;37:1444–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Alba Pale L, Leon Caballero J, Samso Buxareu B, Salgado Serrano P, Perez Sola V. Systematic review of depression in patients with multiple sclerosis and its relationship to interferonbeta treatment. Mult Scler Relat Disord. 2017;17:138–43.

    Article  PubMed  Google Scholar 

  29. Hoyo-Becerra C, Schlaak JF, Hermann DM. Insights from interferon-alpha-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun. 2014;42:222–31.

    Article  CAS  PubMed  Google Scholar 

  30. Coch C, Viviani R, Breitfeld J, Munzer K, Dassler-Plencker J, Holdenrieder S, et al. Interferon-beta-induced changes in neuroimaging phenotypes of appetitive motivation and reactivity to emotional salience. Neuroimage Clin. 2019;24:102020.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mostafavi S, Battle A, Zhu X, Potash JB, Weissman MM, Shi J, et al. Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing. Mol Psychiatry. 2014;19:1267–74.

    Article  CAS  PubMed  Google Scholar 

  32. Zheng LS, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, et al. Mechanisms for interferon-alpha-induced depression and neural stem cell dysfunction. Stem Cell Rep. 2014;3:73–84.

    Article  CAS  Google Scholar 

  33. Wang J, Campbell IL, Zhang H. Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system. Mol Psychiatry. 2008;13:293–301.

    Article  CAS  PubMed  Google Scholar 

  34. Bian Y, Pan Z, Hou Z, Huang C, Li W, Zhao B. Learning, memory, and glial cell changes following recovery from chronic unpredictable stress. Brain Res Bull. 2012;88:471–6.

    Article  PubMed  Google Scholar 

  35. Kopp BL, Wick D, Herman JP. Differential effects of homotypic vs. heterotypic chronic stress regimens on microglial activation in the prefrontal cortex. Physiol Behav. 2013;122:246–52.

    Article  CAS  PubMed  Google Scholar 

  36. London A, Cohen M, Schwartz M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci. 2013;7:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12:623–35.

    Article  CAS  PubMed  Google Scholar 

  38. Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher L, et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 2015;34:1612–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bialas AR, Presumey J, Das A, van der Poel CE, Lapchak PH, Mesin L, et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature. 2017;546:539–43.

    Article  CAS  PubMed  Google Scholar 

  40. Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol. 2009;40:139–56.

    Article  CAS  PubMed  Google Scholar 

  41. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.

    Article  CAS  PubMed  Google Scholar 

  42. Krugers HJ, Lucassen PJ, Karst H, Joels M. Chronic stress effects on hippocampal structure and synaptic function: relevance for depression and normalization by anti-glucocorticoid treatment. Front Synaptic Neurosci. 2010;2:24.

    PubMed  PubMed Central  Google Scholar 

  43. Csabai D, Wiborg O, Czeh B. Reduced synapse and axon numbers in the prefrontal cortex of rats subjected to a chronic stress model for depression. Front Cell Neurosci. 2018;12:24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Suvrathan A, Tomar A, Chattarji S. Effects of chronic and acute stress on rat behaviour in the forced-swim test. Stress. 2010;13:533–40.

    Article  PubMed  Google Scholar 

  45. Ulloa JL, Castaneda P, Berrios C, Diaz-Veliz G, Mora S, Bravo JA, et al. Comparison of the antidepressant sertraline on differential depression-like behaviors elicited by restraint stress and repeated corticosterone administration. Pharm Biochem Behav. 2010;97:213–21.

    Article  CAS  Google Scholar 

  46. Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:112–9.

    Article  CAS  PubMed  Google Scholar 

  47. Bogdanova OV, Kanekar S, D’Anci KE, Renshaw PF. Factors influencing behavior in the forced swim test. Physiol Behav. 2013;118:227–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Henckens MJ, van der Marel K, van der Toorn A, Pillai AG, Fernandez G, Dijkhuizen RM, et al. Stress-induced alterations in large-scale functional networks of the rodent brain. Neuroimage. 2015;105:312–22.

    Article  PubMed  Google Scholar 

  49. Seewoo BJ, Hennessy LA, Feindel KW, Etherington SJ, Croarkin PE, Rodger J. Validation of chronic restraint stress model in young adult rats for the study of depression using longitudinal multimodal MR imaging. eNeuro. 2020;7:ENEURO.0113-20.2020.

  50. Alemu JL, Elberling F, Azam B, Pakkenberg B, Olesen MV. Electroconvulsive treatment prevents chronic restraint stress-induced atrophy of the hippocampal formation—a stereological study. Brain Behav. 2019;9:e01195.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Park MJ, Seo BA, Lee B, Shin HS, Kang MG. Stress-induced changes in social dominance are scaled by AMPA-type glutamate receptor phosphorylation in the medial prefrontal cortex. Sci Rep. 2018;8:15008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Liu Y, Zhuang X, Gou L, Ling X, Tian X, Liu L, et al. Protective effects of nizofenone administration on the cognitive impairments induced by chronic restraint stress in mice. Pharm Biochem Behav. 2013;103:474–80.

    Article  CAS  Google Scholar 

  53. Bowman RE, Beck KD, Luine VN. Chronic stress effects on memory: sex differences in performance and monoaminergic activity. Horm Behav. 2003;43:48–59.

    Article  CAS  PubMed  Google Scholar 

  54. Wang Y, Kan H, Yin Y, Wu W, Hu W, Wang M, et al. Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice. Pharm Biochem Behav. 2014;120:73–81.

    Article  CAS  Google Scholar 

  55. Huang P, Li C, Fu T, Zhao D, Yi Z, Lu Q, et al. Flupirtine attenuates chronic restraint stress-induced cognitive deficits and hippocampal apoptosis in male mice. Behav Brain Res. 2015;288:1–10.

    Article  CAS  PubMed  Google Scholar 

  56. Woo H, Hong CJ, Jung S, Choe S, Yu SW. Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling. Mol Brain. 2018;11:37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Lee T, Jarome T, Li SJ, Kim JJ, Helmstetter FJ. Chronic stress selectively reduces hippocampal volume in rats: a longitudinal magnetic resonance imaging study. Neuroreport. 2009;20:1554–8.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chen Y, Mao Y, Zhou D, Hu X, Wang J, Ma Y. Environmental enrichment and chronic restraint stress in ICR mice: effects on prepulse inhibition of startle and Y-maze spatial recognition memory. Behav Brain Res. 2010;212:49–55.

    Article  PubMed  Google Scholar 

  59. Sanz H, Aponte JJ, Harezlak J, Dong Y, Ayestaran A, Nhabomba A, et al. drLumi: An open-source package to manage data, calibrate, and conduct quality control of multiplex bead-based immunoassays data analysis. PLoS One. 2017;12:e0187901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Pandya CD, Hoda N, Crider A, Peter D, Kutiyanawalla A, Kumar S, et al. Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice. Mol Psychiatry. 2017;22:745–53.

    Article  CAS  PubMed  Google Scholar 

  61. Conrad CD, Galea LA, Kuroda Y, McEwen BS. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav Neurosci. 1996;110:1321–34.

    Article  CAS  PubMed  Google Scholar 

  62. Wright RL, Conrad CD. Chronic stress leaves novelty-seeking behavior intact while impairing spatial recognition memory in the Y-maze. Stress. 2005;8:151–4.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Soper A, Kimura I, Nagaoka S, Konno Y, Yamamoto K, Koyanagi Y, et al. Type I interferon responses by HIV-1 infection: association with disease progression and control. Front Immunol. 2017;8:1823.

    Article  PubMed  CAS  Google Scholar 

  64. Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21:153–60.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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.

    Article  CAS  PubMed  Google Scholar 

  67. Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord. 2012;139:230–9.

    Article  CAS  PubMed  Google Scholar 

  68. Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–3.

    Article  PubMed  Google Scholar 

  69. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21:901–12.

    Article  CAS  PubMed  Google Scholar 

  70. Manikowska K, Mikolajczyk M, Mikolajczak PL, Bobkiewicz-Kozlowska T. The influence of mianserin on TNF-alpha, IL-6 and IL-10 serum levels in rats under chronic mild stress. Pharm Rep. 2014;66:22–7.

    Article  CAS  Google Scholar 

  71. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.

    Article  CAS  PubMed  Google Scholar 

  72. Fernandes A, Miller-Fleming L, Pais TF. Microglia and inflammation: conspiracy, controversy or control? Cell Mol Life Sci. 2014;71:3969–85.

    Article  CAS  PubMed  Google Scholar 

  73. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.

    Article  CAS  PubMed  Google Scholar 

  74. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Presumey J, Bialas AR, Carroll MC. Complement system in neural synapse elimination in development and disease. Adv Immunol. 2017;135:53–79.

    Article  CAS  PubMed  Google Scholar 

  77. Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013;190:3831–8.

    Article  CAS  PubMed  Google Scholar 

  78. Wang Q, Timberlake MA 2nd, Prall K, Dwivedi Y. The recent progress in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2017;77:99–109.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Miller ES, Apple CG, Kannan KB, Funk ZM, Plazas JM, Efron PA, et al. Chronic stress induces persistent low-grade inflammation. Am J Surg. 2019;218:677–83.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Zhu Y, Klomparens EA, Guo S, Geng X. Neuroinflammation caused by mental stress: the effect of chronic restraint stress and acute repeated social defeat stress in mice. Neurol Res. 2019;41:762–9.

    Article  CAS  PubMed  Google Scholar 

  81. Walker FR, Nilsson M, Jones K. Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Curr Drug Targets. 2013;14:1262–76.

    Article  CAS  PubMed  Google Scholar 

  82. Lehmann ML, Weigel TK, Poffenberger CN, Herkenham M. The behavioral sequelae of social defeat require microglia and are driven by oxidative stress in mice. J Neurosci. 2019;39:5594–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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;22:1442–54.

    Article  CAS  PubMed  Google Scholar 

  84. O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 2007;104:1604–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Molnarfi N, Gruaz L, Dayer JM, Burger D. Opposite effects of IFN beta on cytokine homeostasis in LPS- and T cell contact-activated human monocytes. J Neuroimmunol. 2004;146:76–83.

    Article  CAS  PubMed  Google Scholar 

  86. Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol. 2001;2:378–86.

    Article  CAS  PubMed  Google Scholar 

  87. Santha P, Veszelka S, Hoyk Z, Meszaros M, Walter FR, Toth AE, et al. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats. Front Mol Neurosci. 2015;8:88.

    PubMed  Google Scholar 

  88. Blank T, Detje CN, Spiess A, Hagemeyer N, Brendecke SM, Wolfart J, et al. Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity. 2016;44:901–12.

    Article  CAS  PubMed  Google Scholar 

  89. Barner MMM, Brombacher F, Kopf M. Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr Biol. 1998;8:669–72.

    Article  CAS  PubMed  Google Scholar 

  90. Daley JM, Brancato SK, Thomay AA, Reichner JS, Albina JE. The phenotype of murine wound macrophages. J Leukoc Biol. 2010;87:59–67.

    Article  CAS  PubMed  Google Scholar 

  91. Ferrante CJ, Pinhal-Enfield G, Elson G, Cronstein BN, Hasko G, Outram S, et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Ralpha) signaling. Inflammation. 2013;36:921–31.

    Article  CAS  PubMed  Google Scholar 

  92. Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med. 2014;211:1533–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17:131–43.

    Article  CAS  PubMed  Google Scholar 

  94. Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 2019;28:2111–23 e6.

    Article  CAS  PubMed  Google Scholar 

  95. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tenner AJ, Stevens B, Woodruff TM. New tricks for an ancient system: physiological and pathological roles of complement in the CNS. Mol Immunol. 2018;102:3–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Morgan BP. Complement in the pathogenesis of Alzheimer’s disease. Semin Immunopathol. 2018;40:113–24.

    Article  CAS  PubMed  Google Scholar 

  98. Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD. Novel mechanisms and functions of complement. Nat Immunol. 2017;18:1288–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Whalley K. Neurodegenerative disease: complement mediates pathological pruning. Nat Rev Neurosci. 2016;17:336.

    Article  CAS  PubMed  Google Scholar 

  100. Owens T, Khorooshi R, Wlodarczyk A, Asgari N. Interferons in the central nervous system: a few instruments play many tunes. Glia. 2014;62:339–55.

    Article  PubMed  Google Scholar 

  101. Gough DJ, Messina NL, Clarke CJ, Johnstone RW, Levy DE. Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity. 2012;36:166–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Deczkowska A, Baruch K, Schwartz M. Type I/II interferon balance in the regulation of brain physiology and pathology. Trends Immunol. 2016;37:181–92.

    Article  CAS  PubMed  Google Scholar 

  103. Arscott WT, Soltys J, Knight J, Mao-Draayer Y. Interferon beta-1b directly modulates human neural stem/progenitor cell fate. Brain Res. 2011;1413:1–8.

    Article  CAS  PubMed  Google Scholar 

  104. Ejlerskov P, Hultberg JG, Wang J, Carlsson R, Ambjorn M, Kuss M, et al. Lack of Neuronal IFN-beta-IFNAR causes lewy body- and parkinson’s disease-like dementia. Cell. 2015;163:324–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Mult Scler. 2013;19:1765–72.

    Article  CAS  PubMed  Google Scholar 

  106. Reder AT, Feng X. How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms. J Interferon Cytokine Res. 2014;34:589–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kremenchutzky M, Morrow S, Rush C. The safety and efficacy of IFN-beta products for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2007;6:279–88.

    Article  CAS  PubMed  Google Scholar 

  108. Lugaresi A, Rottoli MR, Patti F. Fostering adherence to injectable disease-modifying therapies in multiple sclerosis. Expert Rev Neurother. 2014;14:1029–42.

    Article  CAS  PubMed  Google Scholar 

  109. Reder AT, Oger JF, Kappos L, O’Connor P, Rametta M. Short-term and long-term safety and tolerability of interferon beta-1b in multiple sclerosis. Mult Scler Relat Disord. 2014;3:294–302.

    Article  PubMed  Google Scholar 

  110. Ziemssen T. Multiple sclerosis beyond EDSS: depression and fatigue. J Neurol Sci. 2009;277:S37–41.

    Article  PubMed  Google Scholar 

  111. Ben-Yehuda H, Matcovitch-Natan O, Kertser A, Spinrad A, Prinz M, Amit I, et al. Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress. Mol Psychiatry. 2020;25:1050–67.

    Article  CAS  PubMed  Google Scholar 

  112. Goodbourn S. The regulation of beta-interferon gene expression. Semin Cancer Biol. 1990;1:89–95.

    CAS  PubMed  Google Scholar 

  113. Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008;26:535–84.

    Article  CAS  PubMed  Google Scholar 

  114. Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA. 2010;107:2669–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rosenkranz JA, Venheim ER, Padival M. Chronic stress causes amygdala hyperexcitability in rodents. Biol Psychiatry. 2010;67:1128–36.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Zhang W, Rosenkranz JA. Repeated restraint stress increases basolateral amygdala neuronal activity in an age-dependent manner. Neuroscience. 2012;226:459–74.

    Article  CAS  PubMed  Google Scholar 

  117. Munshi S, Rosenkranz JA. Effects of peripheral immune challenge on in vivo firing of basolateral amygdala neurons in adult male rats. Neuroscience. 2018;390:174–86.

    Article  CAS  PubMed  Google Scholar 

  118. Munshi S, Loh MK, Ferrara N, DeJoseph MR, Ritger A, Padival M, et al. Repeated stress induces a pro-inflammatory state, increases amygdala neuronal and microglial activation, and causes anxiety in adult male rats. Brain Behav Immun. 2020;84:180–99.

    Article  CAS  PubMed  Google Scholar 

  119. Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP. Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology. 2012;37:1491–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Azzinnari D, Sigrist H, Staehli S, Palme R, Hildebrandt T, Leparc G, et al. Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology. 2014;85:328–41.

    Article  CAS  PubMed  Google Scholar 

  121. Ray B, Gaskins DL, Sajdyk TJ, Spence JP, Fitz SD, Shekhar A, et al. Restraint stress and repeated corticotrophin-releasing factor receptor activation in the amygdala both increase amyloid-beta precursor protein and amyloid-beta peptide but have divergent effects on brain-derived neurotrophic factor and pre-synaptic proteins in the prefrontal cortex of rats. Neuroscience. 2011;184:139–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the funding support from US National Institute of Health/National Institute of Mental Health (NIMH) grants (MH120876 and MH121959), and the Merit Review Award (BX004758) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development to AP. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The research funding support from Augusta University is acknowledged. The authors would like to acknowledge Quebec Suicide Brain Bank for human postmortem tissue samples.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anilkumar Pillai.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tripathi, A., Whitehead, C., Surrao, K. et al. Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway. Mol Psychiatry 26, 3043–3059 (2021). https://doi.org/10.1038/s41380-021-01065-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01065-6

This article is cited by

Search

Quick links