Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia

Activation of the kynurenine pathway may lead to depletion of the serotonin precursor tryptophan, which has been implicated in the neurobiology of depression. This study describes a mechanism whereby lithium inhibits inflammatory tryptophan breakdown. Upon activation, immortalized human microglia showed a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3βS9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in activated cells. Experiments in primary human microglia and human induced pluripotent stem cell (hiPSC)-derived microglia corroborated lithium’s effects. Moreover, IDO activity was reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705. Our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.

[1]  P. S. St George-Hyslop,et al.  TET2 Regulates the Neuroinflammatory Response in Microglia. , 2019, Cell reports.

[2]  S. Narumiya,et al.  The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation , 2018, Neuron.

[3]  Joe H. Necus,et al.  3D 7Li magnetic resonance imaging of brain lithium distribution in bipolar disorder , 2018, Molecular Psychiatry.

[4]  E. Ling,et al.  Production of proinflammatory mediators in activated microglia is synergistically regulated by Notch-1, glycogen synthase kinase (GSK-3β) and NF-κB/p65 signalling , 2017, PloS one.

[5]  Katharine A Smith,et al.  Lithium and suicide in mood disorders: Updated meta‐review of the scientific literature , 2017, Bipolar disorders.

[6]  J. Tiihonen.  Use of lithium in patients with unipolar depression - Author's reply. , 2017, The lancet. Psychiatry.

[7]  Shane W. Kraus,et al.  Is excessive sexual behaviour an addictive disorder? , 2017, The lancet. Psychiatry.

[8]  S. Prakash,et al.  Serotonin syndrome in patients with headache disorders , 2017, BMJ Case Reports.

[9]  T. Outhred,et al.  The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines. , 2017, Journal of affective disorders.

[10]  P. K. Feltes,et al.  Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy , 2017, Journal of psychopharmacology.

[11]  M. Colonna,et al.  Microglia Function in the Central Nervous System During Health and Neurodegeneration. , 2017, Annual review of immunology.

[12]  Michael D. Cahalan,et al.  iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases , 2017, Neuron.

[13]  J. Sheridan,et al.  Microglial recruitment of IL-1β producing monocytes to brain endothelium causes stress-induced anxiety , 2017, Molecular Psychiatry.

[14]  Huaxi Xu,et al.  TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway , 2017, The Journal of Neuroscience.

[15]  H. Wulff,et al.  Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia , 2016, Glia.

[16]  S. Jeon,et al.  Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness? , 2016, World journal of psychiatry.

[17]  R. Simone,et al.  Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells , 2016, Brain, Behavior, and Immunity.

[18]  M. Endres,et al.  Actin dynamics shape microglia effector functions , 2016, Brain Structure and Function.

[19]  R. Faull,et al.  Isolation of highly enriched primary human microglia for functional studies , 2016, Scientific Reports.

[20]  R. Yirmiya,et al.  Depression as a Microglial Disease , 2015, Trends in Neurosciences.

[21]  B. Eynde,et al.  Tryptophan-Degrading Enzymes in Tumoral Immune Resistance , 2015, Front. Immunol..

[22]  R. Parsey,et al.  Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. , 2015, JAMA psychiatry.

[23]  C. H. Ma,et al.  Bipolar/rod-shaped microglia are proliferating microglia with distinct M1/M2 phenotypes , 2014, Scientific Reports.

[24]  G. Turecki,et al.  Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides , 2014, Brain, Behavior, and Immunity.

[25]  Shu Zhang,et al.  Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway , 2014, Journal of Neuroinflammation.

[26]  S. Schmidt,et al.  New Insights into IDO Biology in Bacterial and Viral Infections , 2014, Front. Immunol..

[27]  E. Levanon,et al.  Human housekeeping genes, revisited. , 2013, Trends in genetics : TIG.

[28]  S. Tsirka,et al.  Culturing microglia from the neonatal and adult central nervous system. , 2013, Journal of visualized experiments : JoVE.

[29]  Andrea Cipriani,et al.  Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis , 2013, BMJ.

[30]  T. Miyakawa,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013 .

[31]  R. Belmaker,et al.  Effects of lithium on lipopolysaccharide-induced inflammation in rat primary glia cells , 2012, Innate immunity.

[32]  M. Bauer,et al.  Lithium’s Emerging Role in the Treatment of Refractory Major Depressive Episodes: Augmentation of Antidepressants , 2010, Neuropsychobiology.

[33]  C. Mclean,et al.  In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. , 2010, Journal of neurotrauma.

[34]  C. Hooper,et al.  Inhibiting p53 pathways in microglia attenuates microglial‐evoked neurotoxicity following exposure to Alzheimer peptides , 2010, Journal of neurochemistry.

[35]  Yee‐Shin Lin,et al.  Glycogen synthase kinase‐3 negatively regulates anti‐inflammatory interleukin‐10 for lipopolysaccharide‐induced iNOS/NO biosynthesis and RANTES production in microglial cells , 2009, Immunology.

[36]  Yee‐Shin Lin,et al.  Glycogen Synthase Kinase-3β Facilitates IFN-γ-Induced STAT1 Activation by Regulating Src Homology-2 Domain-Containing Phosphatase 21 , 2009, The Journal of Immunology.

[37]  R. Jope,et al.  Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. , 2009, Cellular signalling.

[38]  D. Chauhan,et al.  Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. , 2008, Blood.

[39]  R. Jope,et al.  Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3* , 2008, Journal of Biological Chemistry.

[40]  F. Abad‐Santos,et al.  Lithium and venlafaxine interaction: a case of serotonin syndrome , 2006, Journal of clinical pharmacy and therapeutics.

[41]  K. Jamison,et al.  Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. , 2004, The American journal of psychiatry.

[42]  R. Jope,et al.  The glamour and gloom of glycogen synthase kinase-3. , 2004, Trends in biochemical sciences.

[43]  J W Yates,et al.  Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. , 2000, Chemistry & biology.

[44]  D. Chuang,et al.  Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[45]  D. Feinstein.  Potentiation of Astroglial Nitric Oxide Synthase Type‐2 Expression by Lithium Chloride , 1998, Journal of neurochemistry.

[46]  R. Komoroski,et al.  The distribution of lithium in rat brain and muscle in vivo by 7Li NMR imaging , 1997, Magnetic resonance in medicine.

[47]  G. Laux,et al.  Serotonin Syndrome after Lithium Add-on Medication to Paroxetine , 1997, Pharmacopsychiatry.

[48]  James R. Woodgett,et al.  Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells , 1996, Current Biology.

[49]  D. Melton,et al.  A molecular mechanism for the effect of lithium on development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[51]  M. E. Ward,et al.  Clinical Pharmacokinetics of Lithium , 1994, Journal of clinical pharmacology.

[52]  P. Cohen,et al.  Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. , 1993, The Biochemical journal.

[53]  J. Woodgett,et al.  Molecular cloning and expression of glycogen synthase kinase‐3/factor A. , 1990, The EMBO journal.

[54]  V. Arango,et al.  Evidence for the 5-HT Hypothesis of Suicide A Review of Post-mortem Studies , 1989, British Journal of Psychiatry.

[55]  M. Linnoila,et al.  Cerebrospinal fluid monoamine metabolites and suicidal behavior in depressed patients. A 5-year follow-up study. , 1989, Archives of general psychiatry.

[56]  J. Nurnberger,et al.  Cerebrospinal fluid and plasma monoamines and their metabolites in euthymic bipolar patients , 1985, Biological Psychiatry.

[57]  B. Müller-Oerlinghausen.  Lithium Long-term Treatment - Does it Act via Serotonin? , 1985, Pharmacopsychiatry.

[58]  M. Åsberg,et al.  5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? , 1976, Archives of general psychiatry.

[59]  G. Sedvall,et al.  The effect of lithium treatment on manic symptoms and levels of monoamine metabolites in cerebrospinal fluid of manic depressive patients , 1975, Psychopharmacologia.

[60]  G. Gessa,et al.  Stimulation of serotonin synthesis by lithium. , 1971, The Journal of pharmacology and experimental therapeutics.

[61]  G. Heninger,et al.  Lithium: clinical effects and cerebrospinal fluid acid monoamine metabolites. , 1977, Communications in psychopharmacology.