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Journal of Neuroinflammation

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Open Access 01-12-2014 | Research

Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway

Authors: Hongquan Dong, Xiang Zhang, Xiaonan Dai, Shunmei Lu, Bo Gui, Wenjie Jin, Susu Zhang, Shu Zhang, Yanning Qian

Published in: Journal of Neuroinflammation | Issue 1/2014

Abstract

Background

Lithium, an effective mood stabilizer for the treatment of bipolar disorders, has been recently suggested to have a role in neuroprotection during neurodegenerative diseases. The pathogenesis of neurological disorders often involves the activation of microglia and associated inflammatory processes. Thus, in this study, we aimed to understand the role of lithium in microglial activation and to elucidate the underlying mechanism(s).

Methods

Primary microglial cells were pretreated with lithium and stimulated with lipopolysaccharide (LPS). The cells were assessed regarding the responses of pro-inflammatory cytokines, and the associated signaling pathways were evaluated.

Results

Lithium significantly inhibited LPS-induced microglial activation and pro-inflammatory cytokine production. Further analysis showed that lithium could activate PI3K/Akt signaling. Analyses of the associated signaling pathways demonstrated that the lithium pretreatment led to the suppression of LPS-induced toll-like receptor 4 (TLR4) expressions via the PI3K/Akt/FoxO1 pathway.

Conclusions

This study demonstrates that lithium can inhibit LPS-induced TLR4 expression and microglial activation through the PI3K/Akt/FoxO1 signaling pathway. These results suggest that lithium plays an important role in microglial activation and neuroinflammation-related diseases, which may lead to a new therapeutic strategy for the treatment of neuroinflammation-related disorders.

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Csuka E, Hans VH, Ammann E, Trentz O, Kossmann T, Morganti-Kossmann MC: Cell activation and inflammatory response following traumatic axonal injury in the rat. Neuroreport. 2000, 11: 2587-2590. 10.1097/00001756-200008030-00047.CrossRefPubMed

Popovich PG: Immunological regulation of neuronal degeneration and regeneration in the injured spinal cord. Prog Brain Res. 2000, 128: 43-58. 10.1016/S0079-6123(00)28006-0.CrossRefPubMed

Gao HM, Liu B, Zhang W, Hong JS: Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci. 2003, 24: 395-401. 10.1016/S0165-6147(03)00176-7.CrossRefPubMed

Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A: Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med. 2005, 11: 146-152. 10.1038/nm1177.CrossRefPubMed

Block ML, Hong JS: Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005, 76: 77-98. 10.1016/j.pneurobio.2005.06.004.CrossRefPubMed

Herrera AJ, Tomas-Camardiel M, Venero JL, Cano J, Machado A: Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons. J Neural Transm. 2005, 112: 111-119. 10.1007/s00702-004-0121-3.CrossRefPubMed

Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, Fenton MJ, Oikawa M, Qureshi N, Monks B, Finberg RW, Ingalls RR, Golenbock DT: Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest. 2000, 105: 497-504. 10.1172/JCI8541.PubMedCentralCrossRefPubMed

Cheong MH, Lee SR, Yoo HS, Jeong JW, Kim GY, Kim WJ, Jung IC, Choi YH: Anti-inflammatory effects of Polygala tenuifolia root through inhibition of NF-kappaB activation in lipopolysaccharide-induced BV2 microglial cells. J Ethnopharmacol. 2011, 137: 1402-1408. 10.1016/j.jep.2011.08.008.CrossRefPubMed

Kettenmann H, Hanisch UK, Noda M, Verkhratsky A: Physiology of microglia. Physiol Rev. 2011, 91: 461-553. 10.1152/physrev.00011.2010.CrossRefPubMed

10.

Yu F, Wang Z, Tchantchou F, Chiu CT, Zhang Y, Chuang DM: Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury. J Neurotrauma. 2012, 29: 362-374. 10.1089/neu.2011.1942.PubMedCentralCrossRefPubMed

11.

Li H, Li Q, Du X, Sun Y, Wang X, Kroemer G, Blomgren K, Zhu C: Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells. J Cereb Blood Flow Metab. 2011, 31: 2106-2115. 10.1038/jcbfm.2011.75.PubMedCentralCrossRefPubMed

12.

Dong H, Zhang W, Zeng X, Hu G, Zhang H, He S, Zhang S: Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. Mol Neurobiol. 2014, 49: 1487-1500. 10.1007/s12035-014-8697-6.CrossRefPubMed

13.

Kim SY, Jeong E, Joung SM, Lee JY: PI3K/Akt contributes to increased expression of Toll-like receptor 4 in macrophages exposed to hypoxic stress. Biochem Biophys Res Commun. 2012, 419: 466-471. 10.1016/j.bbrc.2012.02.015.CrossRefPubMed

14.

Ke B, Shen XD, Ji H, Kamo N, Gao F, Freitas MC, Busuttil RW, Kupiec-Weglinski JW: HO-1-STAT3 axis in mouse liver ischemia/reperfusion injury: regulation of TLR4 innate responses through PI3K/PTEN signaling. J Hepatol. 2012, 56: 359-366. 10.1016/j.jhep.2011.05.023.PubMedCentralCrossRefPubMed

15.

Kang K, Kim YJ, Kim YH, Roh JN, Nam JM, Kim PY, Ryu WS, Lee SH, Yoon BW: Lithium pretreatment reduces brain injury after intracerebral hemorrhage in rats. Neurol Res. 2012, 34: 447-454. 10.1179/1743132812Y.0000000015.CrossRefPubMed

16.

Minghetti L: Role of inflammation in neurodegenerative diseases. Curr Opin Neurol. 2005, 18: 315-321. 10.1097/01.wco.0000169752.54191.97.CrossRefPubMed

17.

Park BS, Lee JO: Recognition of lipopolysaccharide pattern by TLR4 complexes.Exp Mol Med 2013, 45:e66..

18.

Pasare C, Medzhitov R: Toll-like receptors: linking innate and adaptive immunity. Microbes Infect. 2004, 6: 1382-1387. 10.1016/j.micinf.2004.08.018.CrossRefPubMed

19.

Jeong JW, Lee HH, Han MH, Kim GY, Kim WJ, Choi YH: Anti-inflammatory effects of genistein via suppression of the toll-like receptor 4-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglia. Chem Biol Interact. 2014, 212: 30-39. 10.1016/j.cbi.2014.01.012.CrossRefPubMed

20.

He Z, Zhu Y, Jiang H: Toll-like receptor 4 mediates lipopolysaccharide-induced collagen secretion by phosphoinositide3-kinase-Akt pathway in fibroblasts during acute lung injury. J Recept Signal Transduct Res. 2009, 29: 119-125.CrossRefPubMed

21.

Chalecka-Franaszek E, Chuang DM: Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci U S A. 1999, 96: 8745-8750. 10.1073/pnas.96.15.8745.PubMedCentralCrossRefPubMed

22.

Dou H, Ellison B, Bradley J, Kasiyanov A, Poluektova LY, Xiong H, Maggirwar S, Dewhurst S, Gelbard HA, Gendelman HE: Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. J Neurosci. 2005, 25: 8375-8385. 10.1523/JNEUROSCI.2164-05.2005.CrossRefPubMed

23.

Kirshenboim N, Plotkin B, Shlomo SB, Kaidanovich-Beilin O, Eldar-Finkelman H: Lithium-mediated phosphorylation of glycogen synthase kinase-3beta involves PI3 kinase-dependent activation of protein kinase C-alpha. J Mol Neurosci. 2004, 24: 237-245. 10.1385/JMN:24:2:237.CrossRefPubMed

24.

Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET: Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol. 2003, 23: 6027-6036. 10.1128/MCB.23.17.6027-6036.2003.PubMedCentralCrossRefPubMed

25.

Facci L, Stevens DA, Skaper SD: Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity. Neuroreport. 2003, 14: 1467-1470. 10.1097/00001756-200308060-00012.CrossRefPubMed

26.

Molnarfi N, Gruaz L, Dayer JM, Burger D: Opposite regulation of IL-1beta and secreted IL-1 receptor antagonist production by phosphatidylinositide-3 kinases in human monocytes activated by lipopolysaccharides or contact with T cells. J Immunol. 2007, 178: 446-454. 10.4049/jimmunol.178.1.446.CrossRefPubMed

27.

Tsukamoto K, Hazeki K, Hoshi M, Nigorikawa K, Inoue N, Sasaki T, Hazeki O: Critical roles of the p110 beta subtype of phosphoinositide 3-kinase in lipopolysaccharide-induced Akt activation and negative regulation of nitrite production in RAW 264.7 cells. J Immunol. 2008, 180: 2054-2061. 10.4049/jimmunol.180.4.2054.CrossRefPubMed

28.

Kops GJ, Burgering BM: Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med (Berl). 1999, 77: 656-665. 10.1007/s001099900050.CrossRef

29.

Nakae J, Barr V, Accili D: Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J. 2000, 19: 989-996. 10.1093/emboj/19.5.989.PubMedCentralCrossRefPubMed

30.

Barthel A, Schmoll D, Unterman TG: FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab. 2005, 16: 183-189. 10.1016/j.tem.2005.03.010.CrossRefPubMed

31.

Furukawa-Hibi Y, Kobayashi Y, Chen C, Motoyama N: FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid Redox Signal. 2005, 7: 752-760. 10.1089/ars.2005.7.752.CrossRefPubMed

32.

Kim SJ, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CH: Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J Biol Chem. 2005, 280: 22297-22307. 10.1074/jbc.M500540200.CrossRefPubMed

33.

Fabre S, Lang V, Harriague J, Jobart A, Unterman TG, Trautmann A, Bismuth G: Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J Immunol. 2005, 174: 4161-4171. 10.4049/jimmunol.174.7.4161.CrossRefPubMed

34.

Arden KC: FoxOs in tumor suppression and stem cell maintenance. Cell. 2007, 128: 235-237. 10.1016/j.cell.2007.01.009.CrossRefPubMed

35.

Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, DePinho RA, Gilliland DG: FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007, 128: 325-339. 10.1016/j.cell.2007.01.003.CrossRefPubMed

36.

Su D, Coudriet GM, Hyun KD, Lu Y, Perdomo G, Qu S, Slusher S, Tse HM, Piganelli J, Giannoukakis N, Zhang J, Dong HH: FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages. Diabetes. 2009, 58: 2624-2633. 10.2337/db09-0232.PubMedCentralCrossRefPubMed

37.

Fan W, Morinaga H, Kim JJ, Bae E, Spann NJ, Heinz S, Glass CK, Olefsky JM: FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 2010, 29: 4223-4236. 10.1038/emboj.2010.268.PubMedCentralCrossRefPubMed

38.

Saponaro C, Cianciulli A, Calvello R, Dragone T, Iacobazzi F, Panaro MA: The PI3K/Akt pathway is required for LPS activation of microglial cells. Immunopharmacol Immunotoxicol. 2012, 34: 858-865. 10.3109/08923973.2012.665461.CrossRefPubMed

39.

Choi YH, Park HY: Anti-inflammatory effects of spermidine in lipopolysaccharide-stimulated BV2 microglial cells.J Biomed Sci 2012, 19:31..

Title: Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway
Authors: Hongquan Dong
Xiang Zhang
Xiaonan Dai
Shunmei Lu
Bo Gui
Wenjie Jin
Susu Zhang
Shu Zhang
Yanning Qian
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2014
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-014-0140-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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