Journal Article

DZNE-2022-00222

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia.

Göttert, R. ; Fidzinski, P. ; Kraus, L. ; Schneider, U. C. ; Holtkamp, M. ; Endres, M.DZNE* ; Gertz, K. ; Kronenberg, G.

2022
Wiley-Liss Bognor Regis [u.a.]

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Please use a persistent id in citations: doi:10.1002/glia.24123

Abstract: 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.

Keyword(s): 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) ; depression ; kynurenine ; lithium ; microglia ; tryptophan ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Kynurenine ; Tryptophan ; Lithium ; Glycogen Synthase Kinase 3

Note: (CC BY-NC)

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Contributing Institute(s):

1. Coordinator of Clinical Research (AG Endres)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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