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.

The neuroimmunology of social-stress-induced sensitization

Nature Immunology volume 23, pages 1527–1535 (2022)Cite this article

Subjects

Abstract

Myriad clinical findings provide links between chronic stressors, inflammation, and mood disorders. Furthermore, traumatic or chronic exposure to psychological stressors may promote stress sensitization, in which individuals have long-term complications, including increased vulnerability to subsequent stressors. Post-traumatic stress disorder (PTSD) is a clinically relevant example of stress sensitization. PTSD alters neuronal circuitry and mood; however, the mechanisms underlying long-term stress sensitization within this disorder are unclear. Rodent models of chronic social defeat recapitulate several key physiological, immunological, and behavioral responses associated with psychological stress in humans. Repeated social defeat (RSD) uniquely promotes the convergence of neuronal, central inflammatory (microglial), and peripheral immune (monocyte) pathways, leading to prolonged anxiety, social withdrawal, and cognitive impairment. Moreover, RSD promotes stress sensitization, in which mice are highly sensitive to subthreshold stress exposure and recurrence of anxiety weeks after the cessation of stress. Therefore, the purpose of this Review is to discuss the influence of social-defeat stress on the immune system that may underlie stress sensitization within three key cellular compartments: neurons, microglia, and monocytes. Delineating the mechanisms of stress sensitization is critical in understanding and treating conditions such as PTSD.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1: Social defeat stress activates the hypothalamic pituitary adrenal axis and sympathetic nervous system to promote the release of monocytes into circulation.
Fig. 2: Repeated social defeat induces neuronal activation that coordinates peripheral and central immune responses that influence behavior and cognition.
Fig. 3: Overview of repeated social defeat and stress sensitization of central and peripheral immune compartments.
Fig. 4: Microglia are primed and more reactive to peripheral immune challenges after repeated social defeat.

References

  1. Haroon, E., Raison, C. L. & Miller, A. H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37, 137–162 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Koo, J. W. & Duman, R. S. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl Acad. Sci. USA 105, 751–756 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Raison, C. L., Capuron, L. & Miller, A. H. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 27, 24–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pace, T. W. & Heim, C. M. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav. Immun. 25, 6–13 (2012).

    Article  Google Scholar 

  6. Stoddard, F. J. et al. Young burned children: the course of acute stress and physiological and behavioral responses. Am. J. Psychiatry 163, 1084–1090 (2006).

    Article  PubMed  Google Scholar 

  7. Torres-Platas, S. G., Cruceanu, C., Chen, G. G., 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. 42, 50–59 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Schnieder, T. P. et al. Microglia of prefrontal white matter in suicide. J. Neuropathol. Exp. Neurol. 73, 880–890 (2014).

    Article  PubMed  Google Scholar 

  9. Jonker, I., Rosmalen, J. G. M. & Schoevers, R. A. Childhood life events, immune activation and the development of mood and anxiety disorders: the TRAILS study. Transl. Psychiatry 7, e1112 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Köhler, C. A. et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scandinavica 135, 373–387 (2017).

    Article  Google Scholar 

  11. Wang, Z., Mandel, H., Levingston, C. A. & Young, M. R. I. An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of veterans with combat-related PTSD. Hum. Immunol. 77, 652–657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Passos, I. C. et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry 2, 1002–1012 (2015).

    Article  PubMed  Google Scholar 

  13. Miller, G. E. et al. Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers. Brain Behav. Immun. 41, 191–199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Powell, N. D. et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis. Proc. Natl Acad. Sci. USA 110, 16574–16579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cole, S. W., Hawkley, L. C., Arevalo, J. M. & Cacioppo, J. T. Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. Proc. Natl Acad. Sci. USA 108, 3080–3085 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miller, G. E. et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lindqvist, D. et al. Increased circulating blood cell counts in combat-related PTSD: associations with inflammation and PTSD severity. Psychiatry Res 258, 330–336 (2017).

    Article  PubMed  Google Scholar 

  18. Beumer, W. et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J. Leukoc. Biol. 92, 959–975 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Pace, T. W. et al. Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder. Brain Behav. Immun. 26, 13–17 (2011).

    Article  PubMed  Google Scholar 

  20. Gola, H. et al. Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry 13, 40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carvalho, L. A. et al. Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder. Transl. Psychiatry 4, e344 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cole, S. W. et al. Social regulation of gene expression in human leukocytes. Genome Biol. 8, R189 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Katrinli, S. et al. Association of HLA locus alleles with posttraumatic stress disorder. Brain Behav. Immun. 81, 655–658 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Deri, Y. et al. Neuroinflammation in World Trade Center responders at midlife: a pilot study using [18F]-FEPPA PET imaging. Brain Behav. Immun. Health 16, 100287 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Setiawan, E. et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 72, 268–275 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mondelli, V., Vernon, A. C., Turkheimer, F., Dazzan, P. & Pariante, C. M. Brain microglia in psychiatric disorders. Lancet Psychiatry 4, 563–572 (2017).

    Article  PubMed  Google Scholar 

  27. Réus, G. Z. et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300, 141–154 (2015).

    Article  PubMed  Google Scholar 

  28. Bhatt, S. et al. PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies. Nat. Commun. 11, 2360 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hall, C. & Ballachey, E. L. A study of the rat’s behavior in a field. A contribution to method in comparative psychology. University of California Publications in Psychology 6, 1–12 (1932).

    Google Scholar 

  30. Wohleb, E. S. et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J. Neurosci. 31, 6277–6288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sawicki, C. M. et al. Ropivacaine and bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated social defeat stress. Brain Behav. Immun. 69, 113–123 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. McKim, D. B. et al. Neuroinflammatory dynamics underlie memory impairments after repeated social defeat. J. Neurosci. 36, 2590–2604 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McKim, D. B. et al. Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety. Mol. Psychiatry 23, 1421–1431 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl Acad. Sci. USA 111, 16136–16141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Bergamini, G. et al. Chronic social stress induces peripheral and central immune activation, blunted mesolimbic dopamine function, and reduced reward-directed behaviour in mice. Neurobiol. Stress 8, 42–56 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Wohleb, E. S. et al. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol. Psychiatry 75, 970–981 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Shimamoto, A. Social defeat stress, sex, and addiction-like behaviors. Int. Rev. Neurobiol. 140, 271–313 (2018).

    Article  PubMed  Google Scholar 

  40. Golden, S. A., Covington, H. E., Berton, O. & Russo, S. J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6, 1183–1191 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Russo, S. J., Murrough, J. W., Han, M. H., Charney, D. S. & Nestler, E. J. Neurobiology of resilience. Nat. Neurosci. 15, 1475–1484 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Takahashi, A. et al. Establishment of a repeated social defeat stress model in female mice. Sci. Rep. 7, 12838 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tsyglakova, M., McDaniel, D. & Hodes, G. E. Immune mechanisms of stress susceptibility and resilience: lessons from animal models. Front. Neuroendocrinol. 54, 100771 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Anacker, C. et al. Neuroanatomic differences associated with stress susceptibility and resilience. Biol. Psychiatry 79, 840–849 (2016).

    Article  PubMed  Google Scholar 

  46. Wohleb, E. S., Powell, N. D., Godbout, J. P. & Sheridan, J. F. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J. Neurosci. 33, 13820–13833 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Christoffel, D. J. et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J. Neurosci. 31, 314–321 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lisboa, S. F. et al. Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2. Neuropsychopharmacology 43, 1924–1933 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sawicki, C. M. et al. Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain. Neuroscience 302, 151–164 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. DiSabato, D. J. et al. Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress. Mol. Psychiatry 26, 4770–4782 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Ramirez, K., Shea, D. T., McKim, D. B., Reader, B. F. & Sheridan, J. F. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav. Immun. 46, 212–220 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ramirez, K., Niraula, A. & Sheridan, J. F. GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations. Brain Behav. Immun. 51, 154–168 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Bellinger, D. L. et al. Sympathetic modulation of immunity: relevance to disease. Cell Immunol. 252, 27–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hanke, M. L., Powell, N. D., Stiner, L. M., Bailey, M. T. & Sheridan, J. F. β-adrenergic blockade decreases the immunomodulatory effects of social disruption stress. Brain Behav. Immun. 26, 1150–1159 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bellavance, M. A. & Rivest, S. The HPA–immune axis and the immunomodulatory actions of glucocorticoids in the brain. Front Immunol. 5, 136 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Niraula, A., Wang, Y., Godbout, J. P. & Sheridan, J. F. Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. J. Neurosci. 38, 2328–2340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wohleb, E. S. et al. Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior. J. Neurosci. 34, 2583–2591 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bailey, M. T., Engler, H., Powell, N. D., Padgett, D. A. & Sheridan, J. F. Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1180–R1190 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Niraula, A., Witcher, K. G., Sheridan, J. F. & Godbout, J. P. Interleukin-6 induced by social stress promotes a unique transcriptional signature in the monocytes that facilitate anxiety. Biol. Psychiatry 85, 679–689 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Voorhees, J. L. et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS ONE 8, e58488 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhou, D., Kusnecov, A. W., Shurin, M. R., DePaoli, M. & Rabin, B. S. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic–pituitary–adrenal axis. Endocrinology 133, 2523–2530 (1993).

    Article  CAS  PubMed  Google Scholar 

  62. Sawicki, C. M. et al. Microglia promote increased pain behavior through enhanced inflammation in the spinal cord during repeated social defeat stress. J. Neurosci. 39, 1139–1149 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu, X. et al. Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. Immunity 50, 317–333 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Takahashi, A. et al. Neuromodulatory effect of interleukin 1β in the dorsal raphe nucleus on individual differences in aggression. Mol. Psychiatry 27, 2563–2579 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Guo, Y. Y. et al. Scutellarin ameliorates the stress-induced anxiety-like behaviors in mice by regulating neurotransmitters. Phytother. Res. 35, 3936–3944 (2021).

    Article  CAS  PubMed  Google Scholar 

  66. Wu, Y. P. et al. Predator stress-induced depression is associated with inhibition of hippocampal neurogenesis in adult male mice. Neural Regen. Res. 14, 298–305 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Poulos, A. M. et al. Amnesia for early life stress does not preclude the adult development of posttraumatic stress disorder symptoms in rats. Biol. Psychiatry 76, 306–314 (2014).

    Article  PubMed  Google Scholar 

  68. Nahvi, R. J., Nwokafor, C., Serova, L. I. & Sabban, E. L. Single prolonged stress as a prospective model for posttraumatic stress disorder in females. Front Behav. Neurosci. 13, 17 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang, J. et al. IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis. Sci. Adv. 7, abb9888 (2021).

    Article  Google Scholar 

  70. Weber, M. D. et al. The influence of microglial elimination and repopulation on stress sensitization induced by repeated social defeat. Biol. Psychiatry 85, 667–678 (2019).

    Article  PubMed  Google Scholar 

  71. McKim, D. B. et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol. Psychiatry 79, 803–813 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Harkness, K. L., Hayden, E. P. & Lopez-Duran, N. L. Stress sensitivity and stress sensitization in psychopathology: an introduction to the special section. J. Abnorm. Psychol. 124, 1–3 (2015).

    Article  PubMed  Google Scholar 

  73. Bandoli, G. et al. Childhood adversity, adult stress, and the risk of major depression or generalized anxiety disorder in US soldiers: a test of the stress sensitization hypothesis. Psychol. Med. 47, 2379–2392 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Park, Y. M., Shekhtman, T. & Kelsoe, J. R. Effect of the type and number of adverse childhood experiences and the timing of adverse experiences on clinical outcomes in individuals with bipolar disorder. Brain Sci. 10, 254 (2020).

    Article  PubMed Central  Google Scholar 

  75. Hammen, C., Henry, R. & Daley, S. E. Depression and sensitization to stressors among young women as a function of childhood adversity. J. Consult Clin. Psychol. 68, 782–787 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. McKim, D. B. et al. Social stress mobilizes hematopoietic stem cells to establish persistent splenic myelopoiesis. Cell Rep. 25, 2552–2562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Logue, M. W. et al. Smaller hippocampal volume in posttraumatic stress disorder: a multisite ENIGMA-PGC study: subcortical volumetry results from posttraumatic stress disorder consortia. Biol. Psychiatry 83, 244–253 (2018).

    Article  PubMed  Google Scholar 

  78. Badura-Brack, A. et al. Veterans with PTSD demonstrate amygdala hyperactivity while viewing threatening faces: a MEG study. Biol. Psychol. 132, 228–232 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Vaiva, G. et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol. Psychiatry 54, 947–949 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Raut, S. B. et al. Effects of propranolol on the modification of trauma memory reconsolidation in PTSD patients: a systematic review and meta-analysis. J. Psychiatr. Res 150, 246–256 (2022).

    Article  PubMed  Google Scholar 

  81. Gandolfi, D. et al. Activation of the CREB/c-Fos pathway during long-term synaptic plasticity in the cerebellum granular layer. Front Cell Neurosci. 11, 184 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Niraula, A., Sheridan, J. F. & Godbout, J. P. Microglia priming with aging and stress. Neuropsychopharmacology 42, 318–333 (2017).

    Article  PubMed  Google Scholar 

  83. Fenn, A. M. et al. Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol. Psychiatry 76, 575–584 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Réu, P. et al. The lifespan and turnover of microglia in the human brain. Cell Rep. 20, 779–784 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Godbout, J. P. et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 19, 1329–1331 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Godbout, J. P. et al. Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, 2341–2351 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Norden, D. M., Trojanowski, P. J., Villanueva, E., Navarro, E. & Godbout, J. P. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia 64, 300–316 (2016).

    Article  PubMed  Google Scholar 

  89. Wohleb, E. S. et al. Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology 37, 1491–1505 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Iwata, M. et al. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol. Psychiatry 80, 12–22 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Avitsur, R., Stark, J. L., Dhabhar, F. S., Padgett, D. A. & Sheridan, J. F. Social disruption-induced glucocorticoid resistance: kinetics and site specificity. J. Neuroimmunol. 124, 54–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shand, F. H. et al. Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. Proc. Natl Acad. Sci. USA 111, 7771–7776 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Weber, G. F. et al. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347, 1260–1265 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Robbins, C. S. et al. Extramedullary hematopoiesis generates Ly-6Chigh monocytes that infiltrate atherosclerotic lesions. Circulation 125, 364–U415 (2012).

    Article  PubMed  Google Scholar 

  98. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Feng, X. et al. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight 2, e91229 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by NIMH grants R01-MH-119670 and R56-MH116670 (to J. P. G. and J. F. S.). C. M. S. was supported by both NIDCR Training Grant T32-DE014320 and F30-DE026075.

Author information

Authors and Affiliations

  1. Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Rebecca G. Biltz, John F. Sheridan & Jonathan P. Godbout

  2. Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA

    Caroline M. Sawicki & John F. Sheridan

  3. Chronic Brain Injury Program, The Ohio State University, Columbus, OH, USA

    John F. Sheridan & Jonathan P. Godbout

  4. Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    John F. Sheridan & Jonathan P. Godbout

Authors
  1. Rebecca G. Biltz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline M. Sawicki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John F. Sheridan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan P. Godbout
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to John F. Sheridan or Jonathan P. Godbout.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Immunology thanks Robert Dantzer, Caroline Menard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Laurie A. Dempsey, in collaboration with the Nature Immunology team.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Biltz, R.G., Sawicki, C.M., Sheridan, J.F. et al. The neuroimmunology of social-stress-induced sensitization. Nat Immunol 23, 1527–1535 (2022). https://doi.org/10.1038/s41590-022-01321-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-022-01321-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing