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Inflammation and Depression: Is Immunometabolism the Missing Link?

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Immuno-Psychiatry

Abstract

Converging clinical and preclinical evidence points to the existence of a subtype of depression associated with low-grade inflammation. This form of depression is characterized by a predominance of somatic symptoms over cognitive and affective symptoms of depression. The possibility of a causal role of inflammation in these symptoms has been investigated mainly in terms of interaction between inflammatory mediators and brain neurotransmitter metabolism, release, and action. More recently, another possibility has emerged in the form of a competition between the energy requirements of the cellular and organismic metabolic reprogramming that is necessary for immune cell activation and those of brain metabolism. In this chapter we will present what has been learned from the progress in immunometabolism, this field of research that examines how the energetic requirements of the proliferation of immune cells and their production of immune communication signals influence their function. We will then examine how this metabolic reprogramming taking place at the periphery and in the brain because of the propagation of the immune response from the periphery to the brain might interfere with brain metabolism, and discuss whether it accounts for the alterations in mitochondrial functions that have been described in preclinical studies of stress and inflammation-induced depression-like behavior and in clinical studies of depressed individuals. We will also present what is known about the sensitivity of the brain dopaminergic neurons to metabolic influences and discuss whether this sensitivity could account for the development of somatic symptoms of depression.

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References

  1. Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R, Shavit Y, Ovadia H, Weidenfeld J, Morag A, Newman ME, Pollmacher T. Illness, cytokines, and depression. Ann N Y Acad Sci. 2000;917:478–87.

    Article  CAS  PubMed  Google Scholar 

  2. Maes M, Smith R, Scharpe S. The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology. 1995;20:111–6.

    Article  CAS  PubMed  Google Scholar 

  3. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988;12:123–37.

    Article  CAS  PubMed  Google Scholar 

  5. Adelman JS, Martin LB. Vertebrate sickness behaviors: adaptive and integrated neuroendocrine immune responses. Integr Comp Biol. 2009;49:202–14.

    Article  CAS  PubMed  Google Scholar 

  6. Demas GE, Carlton ED. Ecoimmunology for psychoneuroimmunologists: considering context in neuroendocrine-immune-behavior interactions. Brain Behav Immun. 2015;44:9–16.

    Article  CAS  PubMed  Google Scholar 

  7. Hawley DM, Etienne RS, Ezenwa VO, Jolles AE. Does animal behavior underlie covariation between hosts’ exposure to infectious agents and susceptibility to infection? Implications for disease dynamics. Integr Comp Biol. 2011;51:528–39.

    Article  PubMed  Google Scholar 

  8. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Franz EA, Gillett G. John Hughlings Jackson’s evolutionary neurology: a unifying framework for cognitive neuroscience. Brain. 2011;134:3114–20.

    Article  PubMed  Google Scholar 

  10. Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiat. 2015;72:603–11.

    Article  Google Scholar 

  11. Critchley HD, Harrison NA. Visceral influences on brain and behavior. Neuron. 2013;77:624–38.

    Article  CAS  PubMed  Google Scholar 

  12. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, Critchley HD. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66:415–22.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Ghosh S, Castillo E, Frias ES, Swanson RA. Bioenergetic regulation of microglia. Glia. 2018;66:1200–12.

    Article  PubMed  Google Scholar 

  16. Ryan DG, O’Neill LAJ. Krebs cycle reborn in macrophage immunometabolism. Annu Rev Immunol. 2020;38:289–313.

    Article  CAS  PubMed  Google Scholar 

  17. McIntosh A, Mela V, Harty C, Minogue AM, Costello DA, Kerskens C, Lynch MA. Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice. Brain Pathol. 2019;29:606–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. van der Poel M, Ulas T, Mizee MR, Hsiao CC, Miedema SSM, Adelia, Schuurman KG, Helder B, Tas SW, Schultze JL, Hamann J, Huitinga I. Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun. 2019;10:1139.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Mela V, Mota BC, Milner M, McGinley A, Mills KHG, Kelly AM, Lynch MA. Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells. Brain Behav Immun. 2020;87:413–28.

    Article  CAS  PubMed  Google Scholar 

  20. Porporato PE. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis. 2016;5:e200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rohm M, Zeigerer A, Machado J, Herzig S. Energy metabolism in cachexia. EMBO Rep. 2019;20:e47258.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Dumas JF, Goupille C, Julienne CM, Pinault M, Chevalier S, Bougnoux P, Servais S, Couet C. Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis. J Hepatol. 2011;54:320–7.

    Article  CAS  PubMed  Google Scholar 

  23. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17:233–47.

    Article  CAS  PubMed  Google Scholar 

  24. Munck A. Glucocorticoid inhibition of glucose uptake by peripheral tissues: old and new evidence, molecular mechanisms, and physiological significance. Perspect Biol Med. 1971;14:265–9.

    Article  CAS  PubMed  Google Scholar 

  25. Du J, McEwen B, Manji HK. Glucocorticoid receptors modulate mitochondrial function: a novel mechanism for neuroprotection. Commun Integr Biol. 2009;2:350–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Peters A, Schweiger U, Pellerin L, Hubold C, Oltmanns KM, Conrad M, Schultes B, Born J, Fehm HL. The selfish brain: competition for energy resources. Neurosci Biobehav Rev. 2004;28:143–80.

    Article  CAS  PubMed  Google Scholar 

  27. Straub RH. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat Rev Rheumatol. 2017;13:743–51.

    Article  CAS  PubMed  Google Scholar 

  28. Wang A, Luan HH, Medzhitov R. An evolutionary perspective on immunometabolism. Science. 2019a;363:6423.

    Article  Google Scholar 

  29. Dienel GA. Brain glucose metabolism: integration of energetics with function. Physiol Rev. 2019;99:949–1045.

    Article  CAS  PubMed  Google Scholar 

  30. Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab. 2012;32:1152–66.

    Article  CAS  PubMed  Google Scholar 

  31. Diaz-Garcia CM, Mongeon R, Lahmann C, Koveal D, Zucker H, Yellen G. Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab. 2017;26(361–374):e4.

    Google Scholar 

  32. Gandhi GK, Cruz NF, Ball KK, Dienel GA. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem. 2009;111:522–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006;98:641–53.

    Article  CAS  PubMed  Google Scholar 

  34. Provent P, Kickler N, Barbier EL, Bergerot A, Farion R, Goury S, Marcaggi P, Segebarth C, Coles JA. The ammonium-induced increase in rat brain lactate concentration is rapid and reversible and is compatible with trafficking and signaling roles for ammonium. J Cereb Blood Flow Metab. 2007;27:1830–40.

    Article  CAS  PubMed  Google Scholar 

  35. Moshkin MP, Akulov AE, Petrovski DV, Saik OV, Petrovskiy ED, Savelov AA, Koptyug IV. Proton magnetic resonance spectroscopy of brain metabolic shifts induced by acute administration of 2-deoxy-d-glucose and lipopolysaccharides. NMR Biomed. 2014;27:399–405.

    Article  CAS  PubMed  Google Scholar 

  36. Verma M, Kipari TMJ, Zhang Z, Man TY, Forster T, Homer NZM, Seckl JR, Holmes MC, Chapman KE. 11beta-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation. Brain Behav Immun. 2018;69:223–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Madrigal JL, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J, Leza JC. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology. 2001;24:420–9.

    Article  CAS  PubMed  Google Scholar 

  38. Rezin GT, Cardoso MR, Goncalves CL, Scaini G, Fraga DB, Riegel RE, Comim CM, Quevedo J, Streck EL. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int. 2008;53:395–400.

    Article  CAS  PubMed  Google Scholar 

  39. Liu W, Zhou C. Corticosterone reduces brain mitochondrial function and expression of mitofusin, BDNF in depression-like rodents regardless of exercise preconditioning. Psychoneuroendocrinology. 2012;37:1057–70.

    Article  CAS  PubMed  Google Scholar 

  40. Chen WJ, Du JK, Hu X, Yu Q, Li DX, Wang CN, Zhu XY, Liu YJ. Protective effects of resveratrol on mitochondrial function in the hippocampus improves inflammation-induced depressive-like behavior. Physiol Behav. 2017;182:54–61.

    Article  CAS  PubMed  Google Scholar 

  41. Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–7.

    Article  CAS  PubMed  Google Scholar 

  42. Jun M, Xiaolong Q, Chaojuan Y, Ruiyuan P, Shukun W, Junbing W, Li H, Hong C, Jinbo C, Rong W, Yajin L, Lanqun M, Fengchao W, Zhiying W, Jianxiong A, Yun W, Xia Z, Chen Z, Zengqiang Y. Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors. Mol Psychiatry. 2018;23:1091.

    Article  CAS  PubMed  Google Scholar 

  43. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A. 2012;109:E197–205.

    Article  CAS  PubMed  Google Scholar 

  44. Nair S, Sobotka KS, Joshi P, Gressens P, Fleiss B, Thornton C, Mallard C, Hagberg H. Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo. Glia. 2019;67:1047–61.

    Article  PubMed  Google Scholar 

  45. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa ASH, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Picard M, McEwen BS. Psychological stress and mitochondria: a systematic review. Psychosom Med. 2018;80:141–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Picard M, McManus MJ, Gray JD, Nasca C, Moffat C, Kopinski PK, Seifert EL, McEwen BS, Wallace DC. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress. Proc Natl Acad Sci U S A. 2015;112:E6614–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gong Y, Chai Y, Ding JH, Sun XL, Hu G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci Lett. 2011;488:76–80.

    Article  CAS  PubMed  Google Scholar 

  49. Wen L, Jin Y, Li L, Sun S, Cheng S, Zhang S, Zhang Y, Svenningsson P. Exercise prevents raphe nucleus mitochondrial overactivity in a rat depression model. Physiol Behav. 2014;132:57–65.

    Article  CAS  PubMed  Google Scholar 

  50. Gusdon AM, Callio J, Distefano G, O’Doherty RM, Goodpaster BH, Coen PM, Chu CT. Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Exp Gerontol. 2017;90:1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Memme JM, Erlich AT, Phukan G, Hood DA. Exercise and mitochondrial health. J Physiol. 2019;599:803–17.

    Article  PubMed  CAS  Google Scholar 

  52. Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM. Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol (1985). 2011;111:1066–71.

    Article  CAS  Google Scholar 

  53. Aguiar AS Jr, Stragier E, da Luz Scheffer D, Remor AP, Oliveira PA, Prediger RD, Latini A, Raisman-Vozari R, Mongeau R, Lanfumey L. Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behavior of mice. Neuroscience. 2014;271:56–63.

    Article  CAS  PubMed  Google Scholar 

  54. Xu Z, Guo X, Yang Y, Tucker D, Lu Y, Xin N, Zhang G, Yang L, Li J, Du X, Zhang Q, Xu X. Low-level laser irradiation improves depression-like behaviors in mice. Mol Neurobiol. 2017;54:4551–9.

    Article  CAS  PubMed  Google Scholar 

  55. Kim Y, McGee S, Czeczor JK, Walker AJ, Kale RP, Kouzani AZ, Walder K, Berk M, Tye SJ. Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects. Transl Psychiatry. 2016;6:e842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bhattacharya A, Jones DNC. Emerging role of the P2X7-NLRP3-IL1beta pathway in mood disorders. Psychoneuroendocrinology. 2018;98:95–100.

    Article  CAS  PubMed  Google Scholar 

  57. Cui QQ, Hu ZL, Hu YL, Chen X, Wang J, Mao L, Lu XJ, Ni M, Chen JG, Wang F. Hippocampal CD39/ENTPD1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP. EMBO Rep. 2020;21:e47857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gamaro GD, Streck EL, Matte C, Prediger ME, Wyse AT, Dalmaz C. Reduction of hippocampal Na+, K+-ATPase activity in rats subjected to an experimental model of depression. Neurochem Res. 2003;28:1339–44.

    Article  CAS  PubMed  Google Scholar 

  59. Wang Y, Ni J, Gao C, Xie L, Zhai L, Cui G, Yin X. Mitochondrial transplantation attenuates lipopolysaccharide- induced depression-like behaviors. Prog Neuro-Psychopharmacol Biol Psychiatry. 2019b;93:240–9.

    Article  CAS  Google Scholar 

  60. Demarest TG, McCarthy MM. Sex differences in mitochondrial (dys)function: implications for neuroprotection. J Bioenerg Biomembr. 2015;47:173–88.

    Article  CAS  PubMed  Google Scholar 

  61. Shimamoto A, Rappeneau V. Sex-dependent mental illnesses and mitochondria. Schizophr Res. 2017;187:38–46.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand. 2000;101:11–20.

    Article  CAS  PubMed  Google Scholar 

  63. Su L, Cai Y, Xu Y, Dutt A, Shi S, Bramon E. Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies. BMC Psychiatry. 2014;14:321.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Marin SE, Saneto RP. Neuropsychiatric features in primary mitochondrial disease. Neurol Clin. 2016;34:247–94.

    Article  PubMed  Google Scholar 

  65. Morava E, Kozicz T. Mitochondria and the economy of stress (mal)adaptation. Neurosci Biobehav Rev. 2013;37:668–80.

    Article  CAS  PubMed  Google Scholar 

  66. Karabatsiakis A, Bock C, Salinas-Manrique J, Kolassa S, Calzia E, Dietrich DE, Kolassa IT. Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression. Transl Psychiatry. 2014;4:e397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cai N, Chang S, Li Y, Li Q, Hu J, Liang J, Song L, Kretzschmar W, Gan X, Nicod J, Rivera M, Deng H, Du B, Li K, Sang W, Gao J, Gao S, Ha B, Ho HY, Hu C, Hu J, Hu Z, Huang G, Jiang G, Jiang T, Jin W, Li G, Li K, Li Y, Li Y, Li Y, Lin YT, Liu L, Liu T, Liu Y, Liu Y, Lu Y, Lv L, Meng H, Qian P, Sang H, Shen J, Shi J, Sun J, Tao M, Wang G, Wang G, Wang J, Wang L, Wang X, Wang X, Yang H, Yang L, Yin Y, Zhang J, Zhang K, Sun N, Zhang W, Zhang X, Zhang Z, Zhong H, Breen G, Wang J, Marchini J, Chen Y, Xu Q, Xu X, Mott R, Huang GJ, Kendler K, Flint J. Molecular signatures of major depression. Curr Biol. 2015;25:1146–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kim MY, Lee JW, Kang HC, Kim E, Lee DC. Leukocyte mitochondrial DNA (mtDNA) content is associated with depression in old women. Arch Gerontol Geriatr. 2011;53:e218–21.

    Article  CAS  PubMed  Google Scholar 

  69. He Y, Tang J, Li Z, Li H, Liao Y, Tang Y, Tan L, Chen J, Xia K, Chen X. Leukocyte mitochondrial DNA copy number in blood is not associated with major depressive disorder in young adults. PLoS One. 2014;9:e96869.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Wang X, Sundquist K, Rastkhani H, Palmer K, Memon AA, Sundquist J. Association of mitochondrial DNA in peripheral blood with depression, anxiety and stress- and adjustment disorders in primary health care patients. Eur Neuropsychopharmacol. 2017;27:751–8.

    Article  CAS  PubMed  Google Scholar 

  71. Lindqvist D, Fernstrom J, Grudet C, Ljunggren L, Traskman-Bendz L, Ohlsson L, Westrin A. Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity. Transl Psychiatry. 2016;6:e971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kageyama Y, Kasahara T, Kato M, Sakai S, Deguchi Y, Tani M, Kuroda K, Hattori K, Yoshida S, Goto Y, Kinoshita T, Inoue K, Kato T. The relationship between circulating mitochondrial DNA and inflammatory cytokines in patients with major depression. J Affect Disord. 2018;233:15–20.

    Article  CAS  PubMed  Google Scholar 

  73. Lindqvist D, Wolkowitz OM, Picard M, Ohlsson L, Bersani FS, Fernstrom J, Westrin A, Hough CM, Lin J, Reus VI, Epel ES, Mellon SH. Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder. Neuropsychopharmacology. 2018;43:1557–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hummel EM, Hessas E, Muller S, Beiter T, Fisch M, Eibl A, Wolf OT, Giebel B, Platen P, Kumsta R, Moser DA. Cell-free DNA release under psychosocial and physical stress conditions. Transl Psychiatry. 2018;8:236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Trumpff C, Marsland AL, Basualto-Alarcon C, Martin JL, Carroll JE, Sturm G, Vincent AE, Mosharov EV, Gu Z, Kaufman BA, Picard M. Acute psychological stress increases serum circulating cell-free mitochondrial DNA. Psychoneuroendocrinology. 2019;106:268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: depression fans the flames and feasts on the heat. Am J Psychiatry. 2015;172:1075–91.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Marsland AL, Walsh C, Lockwood K, John-Henderson NA. The effects of acute psychological stress on circulating and stimulated inflammatory markers: a systematic review and meta-analysis. Brain Behav Immun. 2017;64:208–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Niraula A, Sheridan JF, Godbout JP. Microglia priming with aging and stress. Neuropsychopharmacology. 2017;42:318–33.

    Article  PubMed  Google Scholar 

  79. 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 

  80. Nakahira K, Hisata S, Choi AM. The roles of mitochondrial damage-associated molecular patterns in diseases. Antioxid Redox Signal. 2015;23:1329–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. West AP. Mitochondrial dysfunction as a trigger of innate immune responses and inflammation. Toxicology. 2017;391:54–63.

    Article  CAS  PubMed  Google Scholar 

  82. Unterholzner L. The interferon response to intracellular DNA: why so many receptors? Immunobiology. 2013;218:1312–21.

    Article  CAS  PubMed  Google Scholar 

  83. Al-Hakeim HK, Al-Kufi SN, Al-Dujaili AH, Maes M. Serum interleukin levels and insulin resistance in major depressive disorder. CNS Neurol Disord Drug Targets. 2018;17:618–25.

    Article  CAS  PubMed  Google Scholar 

  84. Merendino RA, Di Rosa AE, Di Pasquale G, Minciullo PL, Mangraviti C, Costantino A, Ruello A, Gangemi S. Interleukin-18 and CD30 serum levels in patients with moderate-severe depression. Mediat Inflamm. 2002;11:265–7.

    Article  Google Scholar 

  85. Swartz JR, Prather AA, Di Iorio CR, Bogdan R, Hariri AR. A functional Interleukin-18 haplotype predicts depression and anxiety through increased threat-related amygdala reactivity in women but not men. Neuropsychopharmacology. 2017;42:419–26.

    Article  CAS  PubMed  Google Scholar 

  86. Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry. 2004;56:819–24.

    Article  CAS  PubMed  Google Scholar 

  87. Dunphy G, Flannery SM, Almine JF, Connolly DJ, Paulus C, Jonsson KL, Jakobsen MR, Nevels MM, Bowie AG, Unterholzner L. Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-kappaB signaling after nuclear DNA damage. Mol Cell. 2018;71(745–760):e5.

    Google Scholar 

  88. Julian MW, Shao G, Bao S, Knoell DL, Papenfuss TL, VanGundy ZC, Crouser ED. Mitochondrial transcription factor a serves as a danger signal by augmenting plasmacytoid dendritic cell responses to DNA. J Immunol. 2012;189:433–43.

    Article  CAS  PubMed  Google Scholar 

  89. Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB, Amoscato AA, Osipov AN, Belikova NA, Kapralov AA, Kini V, Vlasova II, Zhao Q, Zou M, Di P, Svistunenko DA, Kurnikov IV, Borisenko GG. Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol. 2005;1:223–32.

    Article  CAS  PubMed  Google Scholar 

  90. Bajwa E, Pointer CB, Klegeris A. The role of mitochondrial damage-associated molecular patterns in chronic neuroinflammation. Mediat Inflamm. 2019;2019:4050796.

    Article  CAS  Google Scholar 

  91. Strigo IA, Craig AD. Interoception, homeostatic emotions and sympathovagal balance. Philos Trans R Soc Lond Ser B Biol Sci. 2016;371:20160010.

    Article  Google Scholar 

  92. Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker GM. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun. 2019;76:74–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jokela M, Virtanen M, Batty GD, Kivimaki M. Inflammation and specific symptoms of depression. JAMA Psychiat. 2016;73:87–8.

    Article  Google Scholar 

  94. Kohler-Forsberg O, Buttenschon HN, Tansey KE, Maier W, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer A, Rietschel M, McGuffin P, Aitchison KJ, Uher R, Mors O. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav Immun. 2017;62:344–50.

    Article  CAS  PubMed  Google Scholar 

  95. Felger JC, Treadway MT. Inflammation effects on motivation and motor activity: role of dopamine. Neuropsychopharmacology. 2017;42:216–41.

    Article  CAS  PubMed  Google Scholar 

  96. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68:815–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76:470–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Treadway MT, Zald DH. Parsing anhedonia: translational models of reward-processing deficits in psychopathology. Curr Dir Psychol Sci. 2013;22:244–9.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Tsutsui-Kimura I, Natsubori A, Mori M, Kobayashi K, Drew MR, de Kerchove d’Exaerde A, Mimura M, Tanaka KF. Distinct roles of ventromedial versus ventrolateral striatal medium spiny neurons in reward-oriented behavior. Curr Biol. 2017;27(3042–3048):e4.

    Google Scholar 

  100. Felger JC, Mun J, Kimmel HL, Nye JA, Drake DF, Hernandez CR, Freeman AA, Rye DB, Goodman MM, Howell LL, Miller AH. Chronic interferon-alpha decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology. 2013;38:2179–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nunes EJ, Randall PA, Estrada A, Epling B, Hart EE, Lee CA, Baqi Y, Muller CE, Correa M, Salamone JD. Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/chow feeding choice task. Psychopharmacology. 2014;231:727–36.

    Article  CAS  PubMed  Google Scholar 

  102. Yohn SE, Arif Y, Haley A, Tripodi G, Baqi Y, Muller CE, Miguel NS, Correa M, Salamone JD. Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization. Psychopharmacology. 2016;233:3575–86.

    Article  CAS  PubMed  Google Scholar 

  103. Vichaya EG, Hunt SC, Dantzer R. Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. Neuropsychopharmacology. 2014;39:2884–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Harrison NA, Voon V, Cercignani M, Cooper EA, Pessiglione M, Critchley HD. A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards. Biol Psychiatry. 2016;80:73–81.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Lasselin J, Treadway MT, Lacourt TE, Soop A, Olsson MJ, Karshikoff B, Paues-Goranson S, Axelsson J, Dantzer R, Lekander M. Lipopolysaccharide alters motivated behavior in a monetary reward task: a randomized trial. Neuropsychopharmacology. 2017;42:801–10.

    Article  CAS  PubMed  Google Scholar 

  106. Vichaya EG, Dantzer R. Inflammation-induced motivational changes: perspective gained by evaluating positive and negative valence systems. Curr Opin Behav Sci. 2018;22:90–5.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Eisenberger NI, Moieni M, Inagaki TK, Muscatell KA, Irwin MR. In sickness and in health: the co-regulation of inflammation and social behavior. Neuropsychopharmacology. 2017;42:242–53.

    Article  CAS  PubMed  Google Scholar 

  108. Treadway MT, Cooper JA, Miller AH. Can’t or Won’t? Immunometabolic constraints on dopaminergic drive. Trends Cogn Sci. 2019;23:435–48.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Abou-Sleiman PM, Muqit MM, Wood NW. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci. 2006;7:207–19.

    Article  CAS  PubMed  Google Scholar 

  110. Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, Tourlomousis P, Dabritz JHM, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O’Neill LA. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167(457–470):e13.

    Google Scholar 

  111. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151–70.

    Article  CAS  PubMed  Google Scholar 

  112. Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, Cass WA, Sullivan PG, Bing G. Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem. 2007;100:1375–86.

    Article  CAS  PubMed  Google Scholar 

  113. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–62.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40:200–10.

    Article  CAS  PubMed  Google Scholar 

  115. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018;561:258–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L, Fahmy AM, Ducrot C, Laplante A, Bourque MJ, Zhu L, Cayrol R, Le Campion A, McBride HM, Gruenheid S, Trudeau LE, Desjardins M. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1(−/−) mice. Nature. 2019;571:565–9.

    Article  CAS  PubMed  Google Scholar 

  117. Carneiro-Nascimento S, Opacka-Juffry J, Costabile A, Boyle CN, Herde AM, Ametamey SM, Sigrist H, Pryce CR, Patterson M. Chronic social stress in mice alters energy status including higher glucose need but lower brain utilization. Psychoneuroendocrinology. 2020;119:104747.

    Article  CAS  PubMed  Google Scholar 

  118. Kapetanovic R, Afroz SF, Ramnath D, Lawrence GM, Okada T, Curson JE, de Bruin J, Fairlie DP, Schroder K, St John JC, Blumenthal A, Sweet MJ. Lipopolysaccharide promotes Drp1-dependent mitochondrial fission and associated inflammatory responses in macrophages. Immunol Cell Biol. 2020;98:528–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Katoh M, Wu B, Nguyen HB, Thai TQ, Yamasaki R, Lu H, Rietsch AM, Zorlu MM, Shinozaki Y, Saitoh Y, Saitoh S, Sakoh T, Ikenaka K, Koizumi S, Ransohoff RM, Ohno N. Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation. Sci Rep. 2017;7:4942.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Harland M, Torres S, Liu J, Wang X. Neuronal mitochondria modulation of LPS-induced neuroinflammation. J Neurosci. 2020;40:1756–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SHR, Saudou F, Mattson MP, Swerdlow RH, Millan MJ. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020;19:609–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, Sherif M, Ahn KH, D’Souza DC, Formica R, Southwick SM, Duman RS, Sanacora G, Krystal JH. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology. 2020;45:990–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Funded by a graduate fellowship to AC (National Council for Scientific and Technological Development SWE 206541), a NARSAD Distinguished Investigator Award to RD, grants from the National Institutes of Health (R01 CA193522 and R01 NS073939), and an MD Anderson Cancer Support Grant (P30 CA016672).

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Dantzer, R., Casaril, A., Vichaya, E. (2021). Inflammation and Depression: Is Immunometabolism the Missing Link?. In: Berk, M., Leboyer, M., Sommer, I.E. (eds) Immuno-Psychiatry. Springer, Cham. https://doi.org/10.1007/978-3-030-71229-7_16

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