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

Autor:	Göttert R; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Center for Stroke Research Berlin (CSB), Berlin, Germany., Fidzinski P; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Epilepsy-Center Berlin-Brandenburg, Berlin, Germany.; NeuroCure Cluster of Excellence, Berlin, Germany., Kraus L; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Epilepsy-Center Berlin-Brandenburg, Berlin, Germany., Schneider UC; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurochirurgie, Berlin, Germany., Holtkamp M; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Epilepsy-Center Berlin-Brandenburg, Berlin, Germany., Endres M; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Center for Stroke Research Berlin (CSB), Berlin, Germany.; NeuroCure Cluster of Excellence, Berlin, Germany.; German Center for Neurodegenerative Diseases (DZNE), Partner Site Berlin, Berlin, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany., Gertz K; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Center for Stroke Research Berlin (CSB), Berlin, Germany., Kronenberg G; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Neurologie und Abteilung für Experimentelle Neurologie, Berlin, Germany.; Center for Stroke Research Berlin (CSB), Berlin, Germany.; College of Life Sciences, University of Leicester, Leicester, UK.; Leicestershire Partnership National Health Service Trust, Leicester, UK.; Klinik für Psychiatrie, Psychotherapie und Psychosomatik, Psychiatrische Universitätsklinik Zürich, Zürich, Switzerland.
Jazyk:	angličtina
Zdroj:	Glia [Glia] 2022 Mar; Vol. 70 (3), pp. 558-571. Date of Electronic Publication: 2021 Dec 04.
DOI:	10.1002/glia.24123
Abstrakt:	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 GSK3β S9 phosphorylation and reducing STAT1 S727 and STAT3 Y705 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-STAT1 S727 and P-STAT3 Y705 . 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. (© 2021 The Authors. GLIA published by Wiley Periodicals LLC.)
Databáze:	MEDLINE
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