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Cited by 733Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsStress Responses and Cortisol

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Neuroinflammation and psychiatric illness

Open access
Najjar, Souhel, Pearlman, Daniel M, Alper, Kenneth, Najjar, Amanda, Devinsky, Orrin·2013·Journal of Neuroinflammation
DOI 10.1186/1742-2094-10-43PMC PMC3626880
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Abstract

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.

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Figure 1 Influence of the ‘Th1-Th2 cytokine seesaw’ generated by glial cells and T lymphocytes on tryptophan/kynurenine metabolism-mediated serotonergic and glutamatergic abnormalities in major depressive disorder and schizophrenia. Influence of the ’Th1-Th2 seesaw’ generated by glial cells and T lymphocytes (first of three bracketed sections) on the enzymes controlling tryptophan/kynurenine metabolism (second of three bracketed sections) leading to serotonergic and glutamatergic abnormalities in major depressive disorder and schizophrenia (third of three bracketed sections). Microglial and astroglial IDO is the rate-limiting enzyme catalyzing the conversion of tryptophan to KYN and serotonin to 5HTT. KMO, which is solely expressed by microglia, is the rate-limiting enzyme catalyzing the conversion of KYN to 3-OH-KYN. TDO, which is solely expressed by astroglia, is the rate-limiting enzyme catalyzing the conversion of tryptophan to KYN. KAT, expressed primarily in astroglial processes, is the rate-limiting enzyme catalyzing the conversion of KYN to KYNA. The microglial enzymes IDO and KMO are upregulated by Th1 cytokines and downregulated by Th2 cytokines. An imbalance of the ‘Th1-Th2 seesaw’ shifts kynurenine catabolism either towards microglial quinolinic acid (NMDA agonist) as in major depressive disorder, or towards astroglial kynurenic acid (NMDA antagonist) as in schizophrenia. 5HIAA, 5-Hydroxyindoleacetic acid; α7nAchR, alpha 7 nicotinic acetylcholine receptors; BBB, blood–brain barrier; IDO, indoleamine-2,3-dioxygenase; IL, interleukin; IFN-γ, interferon gamma; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYN, kynurenine; KYNA, kynurenic acid; NMDAR, N-methyl-D-aspartate receptor; TNF-α, tumor necrosis factor alpha; T regs, CD4+CD25+FOXP3+ T regulatory cells; TDO, tryptophan-2,3-dioxygenase; Th, T-helper.
Figure 1 Influence of the ‘Th1-Th2 cytokine seesaw’ generated by glial cells and T lymphocytes on tryptophan/kynurenine metabolism-mediated serotonergic and glutamatergic abnormalities in major depressive disorder and schizophrenia. Influence of the ’Th1-Th2 seesaw’ generated by glial cells and T lymphocytes (first of three bracketed sections) on the enzymes controlling tryptophan/kynurenine metabolism (second of three bracketed sections) leading to serotonergic and glutamatergic abnormalities in major depressive disorder and schizophrenia (third of three bracketed sections). Microglial and astroglial IDO is the rate-limiting enzyme catalyzing the conversion of tryptophan to KYN and serotonin to 5HTT. KMO, which is solely expressed by microglia, is the rate-limiting enzyme catalyzing the conversion of KYN to 3-OH-KYN. TDO, which is solely expressed by astroglia, is the rate-limiting enzyme catalyzing the conversion of tryptophan to KYN. KAT, expressed primarily in astroglial processes, is the rate-limiting enzyme catalyzing the conversion of KYN to KYNA. The microglial enzymes IDO and KMO are upregulated by Th1 cytokines and downregulated by Th2 cytokines. An imbalance of the ‘Th1-Th2 seesaw’ shifts kynurenine catabolism either towards microglial quinolinic acid (NMDA agonist) as in major depressive disorder, or towards astroglial kynurenic acid (NMDA antagonist) as in schizophrenia. 5HIAA, 5-Hydroxyindoleacetic acid; α7nAchR, alpha 7 nicotinic acetylcholine receptors; BBB, blood–brain barrier; IDO, indoleamine-2,3-dioxygenase; IL, interleukin; IFN-γ, interferon gamma; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYN, kynurenine; KYNA, kynurenic acid; NMDAR, N-methyl-D-aspartate receptor; TNF-α, tumor necrosis factor alpha; T regs, CD4+CD25+FOXP3+ T regulatory cells; TDO, tryptophan-2,3-dioxygenase; Th, T-helper.CC BY · PubMed Central
Figure 2 Hypothesis of MDD: excess CNS glutamate may contribute to excess Th1- response promoting neuroprotective microglia. Peripheral resting T lymphocytes constitutively express mGluR5. Activated T lymphocytes, but not resting T lymphocytes, can cross the BBB. In the animal models, the interaction between TCR of activated T lymphocytes and their cognate antigen presenting cells downregulates mGluR5 and induces mGluR1 expressions. Experimental data suggest that excess glutamate can bind to lymphocytic mGluR1 receptors, promoting production of Th1 cytokines. Hypothesis: In some MDD patients, parallel to experimental data, binding of excess CNS glutamate to induced lymphocytic mGluR1 receptors may contribute to an excess Th1 response, including IFN-γ. We further hypothesize that IFN-γ in a small quantity, similar to its in vitro effects on microglia, may induce microglial expression of MHC-II and EAAT-2, allowing microglia to serve as cognate antigen presenting cells and to provide glutamate reuptake function, thereby transforming harmful microglia into neuroprotective phenotype that participate in eliminating excess extracellular glutamate and reducing its excitotoxicity. Therefore, we hypothesize that excess Th1 response in some MDD patients is a double-edged sword; promoting harmful inflammation and serving as a beneficial counter-regulatory mechanism that may limit excess glutamate-related neuroexcitotoxicity? AMPA, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)-propanoic acid; APC, antigen presenting cell; BBB, blood–brain barrier; CNS, central nervous system, EAAT, excitatory amino acid transporter; IDO, indoleamine-2,3-dioxygenase; IFN-γ, interferon gamma; IL, interleukin; KMO, kynurenine 3-monooxygenase; mGluR1/5, metabotropic glutamate receptors 1 and 5; MHC II, major histocompatibility complex class 2; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NR1, glycine site; QA, quinolinic acid; TCR, T-cell receptor; Th, T-helper; TNF-α, tumor necrosis factor alpha.
Figure 2 Hypothesis of MDD: excess CNS glutamate may contribute to excess Th1- response promoting neuroprotective microglia. Peripheral resting T lymphocytes constitutively express mGluR5. Activated T lymphocytes, but not resting T lymphocytes, can cross the BBB. In the animal models, the interaction between TCR of activated T lymphocytes and their cognate antigen presenting cells downregulates mGluR5 and induces mGluR1 expressions. Experimental data suggest that excess glutamate can bind to lymphocytic mGluR1 receptors, promoting production of Th1 cytokines. Hypothesis: In some MDD patients, parallel to experimental data, binding of excess CNS glutamate to induced lymphocytic mGluR1 receptors may contribute to an excess Th1 response, including IFN-γ. We further hypothesize that IFN-γ in a small quantity, similar to its in vitro effects on microglia, may induce microglial expression of MHC-II and EAAT-2, allowing microglia to serve as cognate antigen presenting cells and to provide glutamate reuptake function, thereby transforming harmful microglia into neuroprotective phenotype that participate in eliminating excess extracellular glutamate and reducing its excitotoxicity. Therefore, we hypothesize that excess Th1 response in some MDD patients is a double-edged sword; promoting harmful inflammation and serving as a beneficial counter-regulatory mechanism that may limit excess glutamate-related neuroexcitotoxicity? AMPA, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)-propanoic acid; APC, antigen presenting cell; BBB, blood–brain barrier; CNS, central nervous system, EAAT, excitatory amino acid transporter; IDO, indoleamine-2,3-dioxygenase; IFN-γ, interferon gamma; IL, interleukin; KMO, kynurenine 3-monooxygenase; mGluR1/5, metabotropic glutamate receptors 1 and 5; MHC II, major histocompatibility complex class 2; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NR1, glycine site; QA, quinolinic acid; TCR, T-cell receptor; Th, T-helper; TNF-α, tumor necrosis factor alpha.CC BY · PubMed Central

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Research works printed but not linked: 9

  1. Krishnan R: Unipolar depression in adults: epidemiology, pathogenesis, and neurobiology. In UpToDate. Edited by Basow DS. Waltham, MA: UpToDate; 2013.
  2. Stovall J: Bipolar disorder in adults: epidemiology and diagnosis. In UpToDate. Edited by Basow DS. UpToDate: Waltham; 2013.
  3. Fischer BA, Buchanan RW: Schizophrenia: epidemiology and pathogenesis. In UpToDate. Edited by Basow DS. Waltham, MA: UpToDate; 2013.
  4. Doyle C, Deakin JFW: Fewer astrocytes in frontal cortex in schizophrenia, depression and bipolar disorder. Schizophrenia Res 2002, 53:106.
  5. Uranova NA, Orlovskaya DD, Vostrikov VM, Rachmanova VI: Decreased density of oligodendroglial satellites of pyramidal neurons in layer III in the prefrontal cortex in schizophrenia and mood disorders. Schizophr Res 2002, 53:107.
  6. Najjar S, Pearlman D, Devinsky O, Najjar A, Nadkarni S, Butler T, Zagzag D: Neuropsychiatric autoimmune encephalitis with negative VGKC-complex, NMDAR, and GAD autoantibodies: a case report and literature review, forthcoming. Cogn Behav Neurol in press
  7. Si X, Miguel-Hidalgo JJ, Rajkowska G: GFAP expression is reduced in the dorsolateral prefrontal cortex in depression. In Society for Neuroscience; 2003 . Neuroscience Meeting Planne: New Orleans; 2003.
  8. Legutko B, Mahajan G, Stockmeier CA, Rajkowska G: White matter astrocytes are reduced in depression. In Society for Neuroscience . Neuroscience Meeting Planner: Washington, DC; 2011.
  9. Butler T, Maoz A, Vallabhajosula S, Moeller J, Ichise M, Paresh K, Pervez F, Friedman D, Goldsmith S, Najjar S, Osborne J, Solnes L, Wang X, French J, Thesen T, Devinsky O, Kuzniecky R, Stern E, Silbersweig D: Imaging inflammation in a patient with epilepsy associated with antibodies to glutamic acid decarboxylase [abstract]. In Am Epilepsy Society Abstracts, Volume 2. Baltimore: American Epilepsy Society; 2011:191.

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Metadata

Authors
Najjar, S., Pearlman, D. M., Alper, K., Najjar, A., & Devinsky, O.
Affiliations
  • NYU Langone Health (US)
  • Dartmouth Institute for Health Policy and Clinical Practice (US)
Corresponding author
Najjar, Souhel
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2013-04-01
Volume
10
Issue
1
Pages
43-43
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/1742-2094-10-43
PMC
PMC3626880
OpenAlex
W2097086441
Cited by
733
References
265
Citations by year
2026: 28 · 2025: 59 · 2024: 73 · 2023: 56 · 2022: 74 · 2021: 65 · 2020: 54 · 2019: 57 · 2018: 67 · 2017: 54 · 2016: 53 · 2015: 46 · 2014: 36 · 2013: 10
FWCI
3.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
neuroinflammation, mental illness, autoimmunity, psychosis, major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, glutamatergic system, monoaminergic systems, neurotransmitter dysregulation, neuroimmunology
MeSH terms
Animals, Autoimmune Diseases, Mental Disorders, Humans, Inflammation, Autoimmunity

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