Abstract
Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression.
Key points
-
Rheumatoid arthritis (RA) and depression have overlapping features, including similar implicated immuno-mechanistic pathways.
-
Crosstalk between the peripheral immune response and central nervous system provides compelling evidence of a role for immune-mediated inflammation in the pathophysiology of depression, including in RA.
-
Pro-inflammatory molecules can signal to the brain through humoral routes (via the blood–brain barrier and circumventricular organs) and neural routes (via vagal nerve and dorsal root ganglia afferent signalling).
-
Neuroimmune communication in the brain involves the production of inflammatory proteins by both recruited myeloid cells from the periphery and resident microglial cells and can result in activation of glial cells.
-
The peripheral immune system could modulate neurological processes through various mechanisms, including through modulation of the glutamatergic and serotonergic systems, the kynurenine pathway, inflammasome activation and neuroplasticity.
-
Determining the mechanisms that link immune-mediated disorders such as RA with depression should aid in the identification of molecular targets and development of targeted therapy.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Weyand, C. M. & Goronzy, J. J. The immunology of rheumatoid arthritis. Nat. Immunol. 22, 10–18 (2021).
Felger, J. C. & Lotrich, F. E. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246, 199–229 (2013).
Köhler, O. et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 71, 1381–1391 (2014).
Malhi, G. S. & Mann, J. J. Depression. Lancet 392, 2299–2312 (2018).
Otte, C. et al. Major depressive disorder. Nat. Rev. Dis. Prim. 2, 16065 (2016).
Schramm, E., Klein, D. N., Elsaesser, M., Furukawa, T. A. & Domschke, K. Review of dysthymia and persistent depressive disorder: history, correlates, and clinical implications. Lancet Psychiatry 7, 801–812 (2020).
Pezzato, S. et al. Depression is associated with increased disease activity and higher disability in a large Italian cohort of patients with rheumatoid arthritis. Adv. Rheumatol. 61, 57 (2021).
Rathbun, A. M., Reed, G. W. & Harrold, L. R. The temporal relationship between depression and rheumatoid arthritis disease activity, treatment persistence and response: a systematic review. Rheumatology 52, 1785–1794 (2013).
Matcham, F., Rayner, L., Steer, S. & Hotopf, M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology 52, 2136–2148 (2013).
Sparks, J. A. et al. Depression and subsequent risk for incident rheumatoid arthritis among women. Arthritis Care Res. 73, 78–89 (2021).
Drevets, W. C., Wittenberg, G. M., Bullmore, E. T. & Manji, H. K. Immune targets for therapeutic development in depression: towards precision medicine. Nat. Rev. Drug. Discov. 21, 224–244 (2022).
Leighton, S. P. et al. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. Mol. Psychiatry 23, 48–58 (2018).
Matcham, F. et al. The relationship between depression and biologic treatment response in rheumatoid arthritis: an analysis of the British Society for Rheumatology Biologics Register. Rheumatology 57, 835–843 (2018).
Bullmore, E. The art of medicine: inflamed depression. Lancet 392, 1189–1190 (2018).
Beurel, E., Toups, M. & Nemeroff, C. B. The bidirectional relationship of depression and inflammation: double trouble. Neuron 107, 234–256 (2020).
Nerurkar, L., Siebert, S., McInnes, I. B. & Cavanagh, J. Rheumatoid arthritis and depression: an inflammatory perspective. Lancet Psychiatry 6, 164–173 (2019).
McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).
Jaffe, D. H., Rive, B. & Denee, T. R. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry 19, 247 (2019).
Chiu, W. C., Su, Y. P., Su, K. P. & Chen, P. C. Recurrence of depressive disorders after interferon-induced depression. Transl. Psychiatry 7, e1026 (2017).
Eyre, H. A. et al. A meta-analysis of chemokines in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 68, 1–8 (2016).
Chamberlain, S. R. et al. Treatment-resistant depression and peripheral C-reactive protein. Br. J. Psychiatry 214, 11–19 (2019).
Schett, G., McInnes, I. B. & Neurath, M. F. Reframing immune-mediated inflammatory diseases through signature cytokine hubs. N. Engl. J. Med. 385, 628–639 (2021).
Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018).
Levey, D. F. et al. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat. Neurosci. 24, 954–963 (2021).
Tylee, D. S. et al. Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data. Am. J. Med. Genet. Part. B: Neuropsychiatr. Genet. 177, 641–657 (2018).
Tartter, M., Hammen, C., Bower, J. E., Brennan, P. A. & Cole, S. Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and IL1β in youth. Brain Behav. Immun. 46, 104–111 (2015).
Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016).
Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C. M. & Mondelli, V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol. Psychiatry 21, 642–649 (2016).
Danese, A., Pariante, C. M., Caspi, A., Taylor, A. & Poulton, R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc. Natl Acad. Sci. USA 104, 1319–1324 (2007).
Khandaker, G. M., Pearson, R. M., Zammit, S., Lewis, G. & Jones, P. B. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry 71, 1121–1128 (2014).
Kinne, R. W., Stuhlmüller, B. & Burmester, G. R. Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res. Ther. 9, 224 (2007).
Gracie, J. A. et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J. Clin. Investig. 104, 1393–1401 (1999).
Koo, J. W. & Duman, R. S. Evidence for IL-1 receptor blockade as a therapeutic strategy for the treatment of depression. Curr. Opin. Investig. Drugs 10, 664 (2009).
Drago, A., Crisafulli, C., Calabrò, M. & Serretti, A. Enrichment pathway analysis. The inflammatory genetic background in bipolar disorder. J. Affect. Disord. 179, 88–94 (2015).
Alcocer-Gómez, E. et al. NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun. 36, 111–117 (2014).
Maslanik, T. et al. Commensal bacteria and MAMPs are necessary for stress-induced increases in IL-1β and IL-18 but not IL-6, IL-10 or MCP-1. PLoS One 7, e50636 (2012).
Więdłocha, M. et al. Effect of antidepressant treatment on peripheral inflammation markers — a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 80, 217–226 (2018).
Nakahara, H. et al. Anti-interleukin‐6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 48, 1521–1529 (2003).
Pearle, A. D. et al. Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthr. Cartil. 15, 516–523 (2007).
Fujimoto, M. et al. Interleukin‐6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum. 58, 3710–3719 (2008).
Hodes, G. E., Ménard, C. & Russo, S. J. Integrating Interleukin-6 into depression diagnosis and treatment. Neurobiol. Stress 4, 15–22 (2016).
Yoshimura, R. et al. Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRI-refractory depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 722–726 (2009).
Behrens, F. et al. Characterisation of depressive symptoms in rheumatoid arthritis patients treated with tocilizumab during routine daily care. Clin. Exp, Rheumatol. 40, 551–559 (2022).
Probert, L. TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302, 2–22 (2015).
Osimo, E. F. et al. Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav. Immun. 87, 901–909 (2020).
Abbott, R. et al. Tumour necrosis factor-α inhibitor therapy in chronic physical illness: a systematic review and meta-analysis of the effect on depression and anxiety. J. Psychosom. Res. 79, 175–184 (2015).
Raison, C. L. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31–41 (2013).
Eller, T., Vasar, V., Shlik, J. & Maron, E. Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 445–450 (2008).
Dantzer, R., Konsman, J. P., Bluthé, R. M. & Kelley, K. W. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton. Neurosci. 85, 60–65 (2000).
Udit, S., Blake, K. & Chiu, I. M. Somatosensory and autonomic neuronal regulation of the immune response. Nat. Rev. Neurosci. 23, 157–171 (2022).
Bonaz, B., Sinniger, V. & Pellissier, S. The vagus nerve in the neuro-immune axis: implications in the pathology of the gastrointestinal tract. Front. Immunol. 8, 1452 (2017).
Boadas-Vaello, P. et al. Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets. Spinal Cord 54, 330–340 (2016).
Brydon, L., Harrison, N. A., Walker, C., Steptoe, A. & Critchley, H. D. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol. Psychiatry 63, 1022–1029 (2008).
Blank, T. et al. Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity 44, 901–912 (2016).
Critchley, H. D. & Harrison, N. A. Visceral influences on brain and behavior. Neuron 77, 624–638 (2013).
Harrison, N. A. et al. Quantitative magnetization transfer imaging as a biomarker for effects of systemic inflammation on the brain. Biol. Psychiatry 78, 49–57 (2015).
Strike, P. C. & Steptoe, A. Psychosocial factors in the development of coronary artery disease. Prog. Cardiovasc. Dis. 46, 337–347 (2004).
Tsao, N., Hsu, H. P., Ww, C. M., Liu, C. C. & Lei, H. Y. Tumour necrosis factor-α causes an increase in blood-brain barrier permeability during sepsis. J. Med. Microbiol. 50, 812–821 (2001).
Howerton, A. R. et al. Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity. Biol. Psychiatry 75, 873–883 (2014).
D’Mello, C., Le, T. & Swain, M. G. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factorα signaling during peripheral organ inflammation. J. Neurosci. 29, 2089–2102 (2009).
Garré, J. M., Silva, H. M., Lafaille, J. J. & Yang, G. CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α. Nat. Med. 23, 714–722 (2017).
Vichaya, E. G. et al. Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats. J. Neuroinflammation 17, 172 (2020).
Hanlon, M. M. et al. Rheumatoid arthritis macrophages are primed for inflammation and display bioenergetic and functional alterations. Rheumatology 62, 2611–2620 (2023).
Haubruck, P., Pinto, M. M., Moradi, B., Little, C. B. & Gentek, R. Monocytes, macrophages, and their potential niches in synovial joints–therapeutic targets in post-traumatic osteoarthritis? Front. Immunol. 12, 763702 (2021).
Süß, P. et al. Chronic peripheral inflammation causes a region-specific myeloid response in the central nervous system. Cell Rep. 30, 4082–4095 (2020).
Badimon, A. et al. Negative feedback control of neuronal activity by microglia. Nature 586, 417–423 (2020).
Cugurra, A. et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science 373, eabf7844 (2021).
Herisson, F. et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat. Neurosci. 21, 1209–1217 (2018).
De Biase, L. M. et al. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron 95, 341–356 (2017).
Masuda, T., Sankowski, R., Staszewski, O. & Prinz, M. Microglia heterogeneity in the single-cell era. Cell Rep. 30, 1271–1281 (2020).
Beazley-Long, N. et al. VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis. Brain Behav. Immun. 74, 49–67 (2018).
Lopes, F. et al. Brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis. Brain Behav. Immun. 89, 224–232 (2020).
Sağ, S. et al. Central nervous system involvement in rheumatoid arthritis: possible role of chronic inflammation and TNF blocker therapy. Acta Neurol. Belg. 120, 25–31 (2020).
Yin, H., Liu, N., Sigdel, K. R. & Duan, L. Role of NLRP3 inflammasome in rheumatoid arthritis. Front. Immunol. 13, 931690 (2022).
Li, S. et al. Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice. Cell Rep. 41, 111532 (2022).
Song, Y., Zhou, Y. & Zhou, X. The role of mitophagy in innate immune responses triggered by mitochondrial stress. Cell Commun. Signal. 18, 186 (2020).
Wang, D. et al. P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes. Cell Biosci. 10, 28 (2020).
Bhattacharya, A., Derecki, N. C., Lovenberg, T. W. & Drevets, W. C. Role of neuro-immunological factors in the pathophysiology of mood disorders. Psychopharmacology 233, 1623–1636 (2016).
Zhang, H., Ding, L., Shen, T. & Peng, D. HMGB1 involved in stress-induced depression and its neuroinflammatory priming role: a systematic review. Gen. Psychiatr. 32, e100084 (2019).
Paugh, S. W. et al. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat. Genet. 47, 607–614 (2015).
Van Deventer, H. W. et al. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res. 70, 10161-9 (2010).
Reis, H. J. et al. Neuro-transmitters in the central nervous system & their implication in learning and memory processes. Curr. Med. Chem. 16, 796–840 (2009).
Haroon, E. & Miller, A H. Inflammation effects on brain glutamate in depression: mechanistic considerations and treatment implications. Curr. Top. Behav. Neurosci. 31, 173–198 (2017).
Haroon, E., Miller, A. H. & Sanacora, G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology 42, 193–215 (2017).
Clark, I. A. & Vissel, B. Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents. J. Neuroinflammation 13, 236 (2016).
Massart, R., Mongeau, R. & Lanfumey, L. Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 2485–2494 (2012).
Descarries, L., Riad, M. & Parent, M. Ultrastructure of the serotonin innervation in the mammalian central nervous system. Handb. Behav. Neurosci. 21, 65–101 (2010).
Savitz, J. B. & Drevets, W. C. Neuroreceptor imaging in depression. Neurobiol. Dis. 52, 49–65 (2013).
Couch, Y. et al. Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia. Brain Behav. Immun. 29, 136–146 (2013).
Malynn, S., Campos-Torres, A., Moynagh, P. & Haase, J. The pro-inflammatory cytokine TNF-α regulates the activity and expression of the serotonin transporter (SERT) in astrocytes. Neurochem. Res. 38, 694–704 (2013).
Krishnadas, R. et al. Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans. Brain Behav. Immun. 51, 29–38 (2016).
Ogbechi, J. et al. IDO activation, inflammation and musculoskeletal disease. Exp. Gerontol. 131, 110820 (2020).
Criado, G., Šimelyte, E., Inglis, J. J., Essex, D. & Williams, R. O. Indoleamine 2, 3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis. Arthritis Rheum. 60, 1342–1351 (2009).
Merlo, L. M. et al. IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J. Immunol. 192, 2082–2090 (2014).
Marszalek-Grabska, M. et al. Kynurenine emerges from the shadows – current knowledge on its fate and function. Pharmacol. Ther. 225, 107845 (2021).
Chen, X. et al. Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression. Transl. Psychiatry 11, 456 (2021).
Steiner, J. et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J. Neuroinflammation 8, 94 (2011).
Wirth, T. et al. The sympathetic nervous system modulates CD4+ Foxp3+ regulatory T cells via noradrenaline-dependent apoptosis in a murine model of lymphoproliferative disease. Brain Behav. Immun. 38, 100–110 (2014).
Kawasaki, H. et al. A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor. Allergy 69, 445–452 (2014).
Castrén, E. & Rantamäki, T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev. Neurobiol. 70, 289–297 (2010).
Vetencourt, J. F. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385–388 (2008).
Luan, S., Zhou, B., Wu, Q., Wan, H. & Li, H. Brain-derived neurotrophic factor blood levels after electroconvulsive therapy in patients with major depressive disorder: a systematic review and meta-analysis. Asian J. Psychiatry 51, 101983 (2020).
Pedard, M. et al. A reconciling hypothesis centred on brain-derived neurotrophic factor to explain neuropsychiatric manifestations in rheumatoid arthritis. Rheumatology 60, 1608–1619 (2021).
Liu, B., Liu, J., Wang, M., Zhang, Y. & Li, L. From serotonin to neuroplasticity: evolvement of theories for major depressive disorder. Front. Cell. Neurosci. 11, 305 (2017).
McKinnon, M. C., Yucel, K., Nazarov, A. & MacQueen, G. M. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. J. Psychiatry Neurosci. 34, 41–54 (2009).
Liu, J., Gu, Y., Guo, M. & Ji, X. Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases. CNS Neurosci. Ther. 27, 869–882 (2021).
Andersson, K. M. et al. Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 115, E12063–E12072 (2018).
Pedard, M., Demougeot, C., Prati, C. & Marie, C. Brain-derived neurotrophic factor in adjuvant-induced arthritis in rats. Relationship with inflammation and endothelial dysfunction. Prog. Neuropsychopharmacol. Biol. Psychiatry 82, 249–254 (2018).
Lai, N. S. et al. Increased serum levels of brain-derived neurotrophic factor contribute to inflammatory responses in patients with rheumatoid arthritis. Int. J. Mol. Sci. 22, 1841 (2021).
Ravi, M., Miller, A. H. & Michopoulos, V. The immunology of stress and the impact of inflammation on the brain and behaviour. BJPsych Adv. 27, 158–165 (2021).
Forbes, E. E. et al. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am. J. Psychiatry 166, 64–73 (2009).
Keedwell, P. A., Andrew, C., Williams, S. C., Brammer, M. J. & Phillips, M. L. The neural correlates of anhedonia in major depressive disorder. Biol. Psychiatry 58, 843–853 (2005).
Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).
Matsushita, T. et al. Sustained microglial activation in the area postrema of collagen-induced arthritis mice. Arthritis Res. Ther. 23, 273 (2021).
Lang, S. C. et al. Neurodegeneration enhances the development of arthritis. J. Immunol. 198, 2394–2402 (2017).
Rusznák, K. et al. Experimental arthritis inhibits adult hippocampal neurogenesis in mice. Cells 11, 791 (2022).
Süß, P. et al. Hippocampal structure and function are maintained despite severe innate peripheral inflammation. Brain Behav. Immun. 49, 156–170 (2015).
Sochocka, M., Diniz, B. S. & Leszek, J. Inflammatory response in the CNS: friend or foe? Mol. Neurobiol. 54, 8071–8089 (2017).
Koren, T. et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902–5915 (2021).
Ben-Shaanan, T. L. et al. Modulation of anti-tumor immunity by the brain’s reward system. Nat. Commun. 9, 2723 (2018).
Pastrnak, M., Simkova, E. & Novak, T. Insula activity in resting-state differentiates bipolar from unipolar depression: a systematic review and meta-analysis. Sci. Rep. 11, 16930 (2021).
Hu, P., Lu, Y., Pan, B. X. & Zhang, W. H. New insights into the pivotal role of the amygdala in inflammation-related depression and anxiety disorder. Int. J. Mol. Sci. 23, 11076 (2022).
Nazir, S., Farooq, R. K., Nasir, S., Hanif, R. & Javed, A. Therapeutic effect of thymoquinone on behavioural response to UCMS and neuroinflammation in hippocampus and amygdala in BALB/c mice model. Psychopharmacology 239, 47–58 (2022).
Yang, T. T. et al. Adolescents with major depression demonstrate increased amygdala activation. J. Am. Acad. Child. Adolesc. Psychiatry 49, 42–51 (2010).
Hamilton, J. P. & Gotlib, I. H. Neural substrates of increased memory sensitivity for negative stimuli in major depression. Biol. Psychiatry 63, 1155–1162 (2008).
Davies, K. A. et al. Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms. Mol. Psychiatry 26, 5150–5160 (2021).
Cox, J. G., de Groot, M., Kempton, M. J., Williams, S. C. & Cole, J. H. Comparison of volumetric brain analysis in subjects with rheumatoid arthritis and ulcerative colitis. Preprint at medRxiv https://doi.org/10.1101/2023.03.08.23286980 (2023).
Sunzini, F., Schrepf, A., Clauw, D. J. & Basu, N. The biology of pain: through the rheumatology lens. Arthritis Rheumatol. 75, 650–660 (2023).
Peek, A. L. et al. Brain GABA and glutamate levels across pain conditions: a systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool. Neuroimage 210, 116532 (2020).
Yang, Z. et al. Understanding complex functional wiring patterns in major depressive disorder through brain functional connectome. Transl. Psychiatry 11, 526 (2021).
Kraynak, T. E., Marsland, A. L., Wager, T. D. & Gianaros, P. J. Functional neuroanatomy of peripheral inflammatory physiology: a meta-analysis of human neuroimaging studies. Neurosci. Biobehav. Rev. 94, 76–92 (2018).
Koolschijn, P. C., van Haren, N. E., Lensvelt‐Mulders, G. J., Hulshoff Pol, H. E. & Kahn, R. S. Brain volume abnormalities in major depressive disorder: a meta‐analysis of magnetic resonance imaging studies. Hum. Brain Mapp. 30, 3719–3735 (2009).
Harrison, N. A. et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry 66, 407–414 (2009).
Haroon, E. et al. IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. Neuropsychopharmacology 39, 1777–1785 (2014).
Basu, N. et al. Functional and structural magnetic resonance imaging correlates of fatigue in patients with rheumatoid arthritis. Rheumatology 58, 1822–1830 (2019).
Kitzbichler, M. G. et al. Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks. Mol. Psychiatry 26, 7346–7354 (2021).
Sheline, Y. I. et al. The default mode network and self-referential processes in depression. Proc. Natl Acad. Sci. USA 106, 1942–1947 (2009).
Hess, A. et al. Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. Proc. Natl Acad. Sci. USA 108, 3731–3736 (2011).
Goldsmith, D. R., Rapaport, M. H. & Miller, B. J. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol. Psychiatry 21, 1696–1709 (2016).
Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).
Strawbridge, R. et al. Inflammation and clinical response to treatment in depression: a meta-analysis. Eur. Neuropsychopharmacol. 25, 1532–1543 (2015).
Mac Giollabhui, N., Ng, T. H., Ellman, L. M. & Alloy, L. B. The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression. Mol. Psychiatry 26, 3302–3314 (2021).
Valkanova, V., Ebmeier, K. P. & Allan, C. L. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J. Affect. Disord. 150, 736–744 (2013).
Köhler, C. A. et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scand. 135, 373–387 (2017).
Martínez-Cengotitabengoa, M. et al. Peripheral inflammatory parameters in late-life depression: a systematic review. Int. J. Mol. Sci. 17, 2022 (2016).
Liu, Y., Ho, R. C. & Mak, A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J. Affect. Disord. 139, 230–239 (2012).
Haapakoski, R., Mathieu, J., Ebmeier, K. P., Alenius, H. & Kivimäki, M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. 49, 206–215 (2015).
Hiles, S. A., Baker, A. L., de Malmanche, T. & Attia, J. A meta-analysis of differences in IL-6 and IL-10 between people with and without depression: exploring the causes of heterogeneity. Brain Behav. Immun. 26, 1180–1188 (2012).
Wittenberg, G. M. et al. Effects of immunomodulatory drugs on depressive symptoms: a mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol. Psychiatry 25, 1275–1285 (2020).
Matcham, F. et al. The impact of targeted rheumatoid arthritis pharmacologic treatment on mental health: a systematic review and network meta‐analysis. Arthritis Rheumatol. 70, 1377–1391 (2018).
Kappelmann, N., Lewis, G., Dantzer, R., Jones, P. B. & Khandaker, G. M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatry 23, 335–343 (2018).
Köhler‐Forsberg O, N. et al. Efficacy of anti‐inflammatory treatment on major depressive disorder or depressive symptoms: meta‐analysis of clinical trials. Acta Psychiatr. Scand. 139, 404–419 (2019).
Author information
Authors and Affiliations
Contributions
All authors researched data for the article. J.C., J.B., N.B. and J.C.M.S. wrote the article and reviewed and/or edited the manuscript before submission. J.C. and J.B. contributed substantially to discussion of the content.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Rheumatology thanks Carmine Pariante, James Galloway and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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.
About this article
Cite this article
Brock, J., Basu, N., Schlachetzki, J.C.M. et al. Immune mechanisms of depression in rheumatoid arthritis. Nat Rev Rheumatol 19, 790–804 (2023). https://doi.org/10.1038/s41584-023-01037-w
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-023-01037-w