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000163462 037__ $$aDZNE-2022-00222
000163462 041__ $$aEnglish
000163462 082__ $$a610
000163462 1001_ $$00000-0003-4756-7381$$aGöttert, Ria$$b0
000163462 245__ $$aLithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia.
000163462 260__ $$aBognor Regis [u.a.]$$bWiley-Liss$$c2022
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000163462 520__ $$aDespite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells. Interferon (IFN)-γ, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3βS9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in IFN-γ treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705 . Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.
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000163462 650_7 $$2Other$$adepression
000163462 650_7 $$2Other$$akynurenine
000163462 650_7 $$2Other$$alithium
000163462 650_7 $$2Other$$amicroglia
000163462 650_7 $$2Other$$atryptophan
000163462 650_7 $$2NLM Chemicals$$aIndoleamine-Pyrrole 2,3,-Dioxygenase
000163462 650_7 $$0343-65-7$$2NLM Chemicals$$aKynurenine
000163462 650_7 $$08DUH1N11BX$$2NLM Chemicals$$aTryptophan
000163462 650_7 $$09FN79X2M3F$$2NLM Chemicals$$aLithium
000163462 650_7 $$0EC 2.7.11.26$$2NLM Chemicals$$aGlycogen Synthase Kinase 3
000163462 650_2 $$2MeSH$$aGlycogen Synthase Kinase 3: metabolism
000163462 650_2 $$2MeSH$$aGlycogen Synthase Kinase 3: pharmacology
000163462 650_2 $$2MeSH$$aHumans
000163462 650_2 $$2MeSH$$aIndoleamine-Pyrrole 2,3,-Dioxygenase: genetics
000163462 650_2 $$2MeSH$$aIndoleamine-Pyrrole 2,3,-Dioxygenase: metabolism
000163462 650_2 $$2MeSH$$aIndoleamine-Pyrrole 2,3,-Dioxygenase: pharmacology
000163462 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000163462 650_2 $$2MeSH$$aInflammation: metabolism
000163462 650_2 $$2MeSH$$aKynurenine: metabolism
000163462 650_2 $$2MeSH$$aKynurenine: pharmacology
000163462 650_2 $$2MeSH$$aLithium: metabolism
000163462 650_2 $$2MeSH$$aLithium: pharmacology
000163462 650_2 $$2MeSH$$aMicroglia: metabolism
000163462 650_2 $$2MeSH$$aTryptophan: metabolism
000163462 650_2 $$2MeSH$$aTryptophan: pharmacology
000163462 7001_ $$aFidzinski, Pawel$$b1
000163462 7001_ $$aKraus, Larissa$$b2
000163462 7001_ $$aSchneider, Ulf Christoph$$b3
000163462 7001_ $$aHoltkamp, Martin$$b4
000163462 7001_ $$0P:(DE-2719)2811033$$aEndres, Matthias$$b5$$udzne
000163462 7001_ $$aGertz, Karen$$b6
000163462 7001_ $$aKronenberg, Golo$$b7
000163462 773__ $$0PERI:(DE-600)1474828-9$$a10.1002/glia.24123$$gVol. 70, no. 3, p. 558 - 571$$n3$$p558 - 571$$tGlia$$v70$$x1098-1136$$y2022
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