163462 20240320115518.0 10.1002/glia.24123 doi pmid:34862988 pmid 0894-1491 ISSN 1098-1136 ISSN altmetric:118127089 altmetric DZNE-2022-00222 English 610 Göttert, Ria 0000-0003-4756-7381 0 Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia. Bognor Regis [u.a.] 2022 Wiley-Liss article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1655199546_924 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote (CC BY-NC) Despite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells. Interferon (IFN)-γ, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing 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 IFN-γ treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705 . Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de depression Other kynurenine Other lithium Other microglia Other tryptophan Other Indoleamine-Pyrrole 2,3,-Dioxygenase NLM Chemicals Kynurenine 343-65-7 NLM Chemicals Tryptophan 8DUH1N11BX NLM Chemicals Lithium 9FN79X2M3F NLM Chemicals Glycogen Synthase Kinase 3 EC 2.7.11.26 NLM Chemicals Glycogen Synthase Kinase 3: metabolism MeSH Glycogen Synthase Kinase 3: pharmacology MeSH Humans MeSH Indoleamine-Pyrrole 2,3,-Dioxygenase: genetics MeSH Indoleamine-Pyrrole 2,3,-Dioxygenase: metabolism MeSH Indoleamine-Pyrrole 2,3,-Dioxygenase: pharmacology MeSH Induced Pluripotent Stem Cells: metabolism MeSH Inflammation: metabolism MeSH Kynurenine: metabolism MeSH Kynurenine: pharmacology MeSH Lithium: metabolism MeSH Lithium: pharmacology MeSH Microglia: metabolism MeSH Tryptophan: metabolism MeSH Tryptophan: pharmacology MeSH Fidzinski, Pawel 1 Kraus, Larissa 2 Schneider, Ulf Christoph 3 Holtkamp, Martin 4 Endres, Matthias P:(DE-2719)2811033 5 dzne Gertz, Karen 6 Kronenberg, Golo 7 10.1002/glia.24123 Vol. 70, no. 3, p. 558 - 571 PERI:(DE-600)1474828-9 3 558 - 571 Glia 70 2022 1098-1136 OpenAccess http://pub.dzne.de/record/163462/files/DZNE-2022-00222.pdf OpenAccess pdfa http://pub.dzne.de/record/163462/files/DZNE-2022-00222.pdf?subformat=pdfa oai:pub.dzne.de:163462 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2811033 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 0 2022 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-08 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-08 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-08 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-29 JCR StatID:(DE-HGF)0100 StatID GLIA : 2021 2022-11-08 Creative Commons Attribution-NonCommercial CC BY-NC 4.0 LIC:(DE-HGF)CCBYNC4 HGFVOC DEAL Wiley StatID:(DE-HGF)3001 StatID 2021-01-29 ger WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-29 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-08 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-08 IF >= 5 StatID:(DE-HGF)9905 StatID GLIA : 2021 2022-11-08 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-29 Nationallizenz StatID:(DE-HGF)0420 StatID 2022-11-08 ger DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-08 I:(DE-2719)1811005 AG Endres Coordinator of Clinical Research 0 journal VDB UNRESTRICTED I:(DE-2719)1811005 FullTexts