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FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation

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Abstract

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons and excessive microglial activation in the substantia nigra pars compacta (SNpc). In the present study, we aimed to demonstrate the therapeutic effectiveness of the potent sphingosine-1-phosphate receptor antagonist fingolimod (FTY720) in an animal model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and to identify the potential mechanisms underlying these therapeutic effects. C57BL/6J mice were orally administered FTY720 before subcutaneous injection of MPTP. Open-field and rotarod tests were performed to determine the therapeutic effect of FTY720. The damage to dopaminergic neurons and the production of monoamine neurotransmitters were assessed using immunohistochemistry, high-performance liquid chromatography, and flow cytometry. Immunofluorescence (CD68- positive) and enzyme-linked immunosorbent assay were used to analyze the activation of microglia, and the levels of activated signaling molecules were measured using Western blotting. Our findings indicated that FTY720 significantly attenuated MPTP-induced behavioral deficits, reduced the loss of dopaminergic neurons, and increased dopamine release. FTY720 directly inhibited MPTP-induced microglial activation in the SNpc, suppressed the production of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in BV-2 microglial cells treated with 1-methyl-4-phenylpyridinium (MPP+), and subsequently decreased apoptosis in SH-SY5Y neuroblastoma cells. Moreover, in MPP+-treated BV-2 cells and primary microglia, FTY720 treatment significantly attenuated the increases in the phosphorylation of PI3K/AKT/GSK-3β, reduced ROS generation and p65 activation, and also inhibited the activation of NLRP3 inflammasome and caspase-1. In conclusion, FTY720 may reduce PD progression by inhibiting NLRP3 inflammasome activation via its effects on ROS generation and p65 activation in microglia. These findings provide novel insights into the mechanisms underlying the therapeutic effects of FTY720, suggesting its potential as a novel therapeutic strategy against PD.

FTY720 may reduce ROS production by inhibiting the PI3K/AKT/GSK-3β signaling pathway, while at the same time reducing p65 phosphorylation, thus decreasing NLRP3 inflammasome activation through these two pathways, ultimately reducing microglia activation-induced neuronal damage.

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Abbreviations

5-HIAA:

5-hydroxyindoleacetic acid

5-HT:

5-hydroxytryptamine

6-OHDA:

6-hydroxydopamine

BBB:

Blood-brain barrier

DA:

Dopamine

DOPAC:

3,4-dihydroxy-phenylacetic acid

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine serum

FTY720:

Fingolimod

HPLC:

High performance liquid chromatography

HVA:

Homovanillic acid

Iba-1:

Ionized-calcium–binding adapter molecule 1

IL-6:

Interleukin-6

MPP+ :

1-methyl-4-phenylpyridinium

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NE:

Noradrenaline

OFT:

Open-field test

EDTA:

Ethylenediaminetetracetic acid

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

PFA:

Paraformaldehyde

PP2A:

Protein phosphatase 2A

RT:

Room temperature

S1P:

Sphingosine-1-phosphate

SDS:

Sodium dodecyl sulfate

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α.

References

  • Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791

    Article  CAS  PubMed  Google Scholar 

  • Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC (2009) The "down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of down syndrome. J Neurosci 29:5938–5948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bijur GN, Jope RS (2003) Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. Neuroreport 14:2415–2419

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  CAS  PubMed  Google Scholar 

  • Brinkmann V (2009) FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 158:1173–1182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao K, Liao X, Lu J, Yao S, Wu F, Zhu X, Shi D, Wen S, Liu L, Zhou H (2018) IL-33/ST2 plays a critical role in endothelial cell activation and microglia-mediated neuroinflammation modulation. J Neuroinflammation 15:136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z, Chen S, Liu J (2018) The role of T cells in the pathogenesis of Parkinson's disease. Prog Neurobiol 169:1–23

    Article  CAS  PubMed  Google Scholar 

  • Cianciulli A, Calvello R, Porro C, Trotta T, Salvatore R, Panaro MA (2016) PI3k/Akt signalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-activated microglia. Int Immunopharmacol 36:282–290

    Article  CAS  PubMed  Google Scholar 

  • Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Nunez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21:248–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cristobal I, Madoz-Gurpide J, Manso R, Gonzalez-Alonso P, Rojo F, Garcia-Foncillas J (2016) Potential anti-tumor effects of FTY720 associated with PP2A activation: a brief review. Curr Med Res Opin 32:1137–1141

    Article  CAS  PubMed  Google Scholar 

  • Das A, Arifuzzaman S, Kim SH, Lee YS, Jung KH, Chai YG (2017) FTY720 (fingolimod) regulates key target genes essential for inflammation in microglial cells as defined by high-resolution mRNA sequencing. Neuropharmacology 119:1–14

    Article  CAS  PubMed  Google Scholar 

  • Deora V, Albornoz EA, Zhu K, Woodruff TM, Gordon R (2017) The ketone body β-Hydroxybutyrate does not inhibit Synuclein mediated Inflammasome activation in microglia. J NeuroImmune Pharmacol 12:568–574

    Article  PubMed  Google Scholar 

  • Di Menna L, Molinaro G, Di Nuzzo L, Riozzi B, Zappulla C, Pozzilli C, Turrini R, Caraci F, Copani A, Battaglia G, Nicoletti F, Bruno V (2013) Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacol Res 67:1–9

    Article  CAS  PubMed  Google Scholar 

  • Di Pardo A, Amico E, Favellato M, Castrataro R, Fucile S, Squitieri F, Maglione V (2014) FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease. Hum Mol Genet 23:2251–2265

    Article  CAS  PubMed  Google Scholar 

  • Dong H, Zhang X, Dai X, Lu S, Gui B, Jin W, Zhang S, Zhang S, Qian Y (2014) Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway. J Neuroinflammation 11:140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao F, Liu Y, Li X, Wang Y, Wei D, Jiang W (2012) Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model. Pharmacol Biochem Behav 103:187–196

    Article  CAS  PubMed  Google Scholar 

  • Garris CS, Blaho VA, Hla T, Han MH (2014) Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology 142:347–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH (2010) Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke 41:368–374

    Article  CAS  PubMed  Google Scholar 

  • Heinen A, Beyer F, Tzekova N, Hartung HP, Kury P (2015) Fingolimod induces the transition to a nerve regeneration promoting Schwann cell phenotype. Exp Neurol 271:25–35

    Article  CAS  PubMed  Google Scholar 

  • Hemmati F, Dargahi L, Nasoohi S, Omidbakhsh R, Mohamed Z, Chik Z, Naidu M, Ahmadiani A (2013) Neurorestorative effect of FTY720 in a rat model of Alzheimer's disease: comparison with memantine. Behav Brain Res 252:415–421

    Article  CAS  PubMed  Google Scholar 

  • Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678

    Article  CAS  PubMed  Google Scholar 

  • Hou H, Cao R, Miao J, Sun Y, Liu X, Song X, Guo L (2016) Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice. Int Immunopharmacol 30:171–178

    Article  CAS  PubMed  Google Scholar 

  • Hunter SF, Bowen JD, Reder AT (2016) The direct effects of Fingolimod in the central nervous system: implications for relapsing multiple sclerosis. CNS Drugs 30:135–147

    Article  CAS  PubMed  Google Scholar 

  • Jackson SJ, Giovannoni G, Baker D (2011) Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation 8:76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamilloux Y, Pierini R, Querenet M, Juruj C, Fauchais AL, Jauberteau MO, Jarraud S, Lina G, Etienne J, Roy CR, Henry T, Davoust N, Ader F (2013) Inflammasome activation restricts legionella pneumophila replication in primary microglial cells through flagellin detection. Glia 61:539–549

    Article  PubMed  Google Scholar 

  • Jope RS, Yuskaitis CJ, Beurel E (2007) Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 32:577–595

    Article  CAS  PubMed  Google Scholar 

  • Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401

    Article  CAS  PubMed  Google Scholar 

  • Kempuraj D, Selvakumar GP, Zaheer S, Thangavel R, Ahmed ME, Raikwar S, Govindarajan R, Iyer S, Zaheer A (2017) Cross-talk between glia, neurons and mast cells in Neuroinflammation associated with Parkinson's disease. J NeuroImmune Pharmacol 13:100–112

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim WK, Hwang SY, Oh ES, Piao HZ, Kim KW, Han IO (2004) TGF-beta1 represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity. J Immunol 172:7015–7023

    Article  CAS  PubMed  Google Scholar 

  • King TD, Clodfelder-Miller B, Barksdale KA, Bijur GN (2008) Unregulated mitochondrial GSK3beta activity results in NADH: ubiquinone oxidoreductase deficiency. Neurotox Res 14:367–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinoshita K, Tada Y, Muroi Y, Unno T, Ishii T (2015) Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning. Life Sci 137:28–36

    Article  CAS  PubMed  Google Scholar 

  • Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13:397–411

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Gu Y, Wang H, Yin J, Zheng G, Zhang Z, Lu M, Wang C, He Z (2015a) Overexpression of PP2A inhibitor SET oncoprotein is associated with tumor progression and poor prognosis in human non-small cell lung cancer. Oncotarget 6:14913–14925

    PubMed  PubMed Central  Google Scholar 

  • Liu J, Huang D, Xu J, Tong J, Wang Z, Huang L, Yang Y, Bai X, Wang P, Suo H, Ma Y, Yu M, Fei J, Huang F (2015b) Tiagabine protects dopaminergic neurons against neurotoxins by inhibiting microglial activation. Sci Rep 5:15720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Chen HQ, Huang Y, Qiu YH, Peng YP (2016) Transforming growth factor-beta1 acts via TbetaR-I on microglia to protect against MPP(+)-induced dopaminergic neuronal loss. Brain Behav Immun 51:131–143

    Article  CAS  PubMed  Google Scholar 

  • Martin M, Rehani K, Jope RS, Michalek SM (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6:777–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin I, Dawson VL, Dawson TM (2011) Recent advances in the genetics of Parkinson's disease. Annu Rev Genomics Hum Genet 12:301–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McManus RM, Finucane OM, Wilk MM, Mills K, Lynch MA (2017) FTY720 attenuates infection-induced enhancement of Abeta accumulation in APP/PS1 mice by modulating astrocytic activation. J NeuroImmune Pharmacol 12:670–681

    Article  PubMed  Google Scholar 

  • Montalban X, Comi G, O'Connor P, Gold S, de Vera A, Eckert B, Kappos L (2011) Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study. Mult Scler 17:1341–1350

    Article  CAS  PubMed  Google Scholar 

  • Moon MH, Jeong JK, Lee YJ, Park SY (2013) FTY720 protects neuronal cells from damage induced by human prion protein by inactivating the JNK pathway. Int J Mol Med 32:1387–1393

    Article  CAS  PubMed  Google Scholar 

  • Nakano N, Matsuda S, Ichimura M, Minami A, Ogino M, Murai T, Kitagishi Y (2017) PI3K/AKT signaling mediated by G proteincoupled receptors is involved in neurodegenerative Parkinson's disease (review). Int J Mol Med 39:253–260

    Article  CAS  PubMed  Google Scholar 

  • Noda H, Takeuchi H, Mizuno T, Suzumura A (2013) Fingolimod phosphate promotes the neuroprotective effects of microglia. J Neuroimmunol 256:13–18

    Article  CAS  PubMed  Google Scholar 

  • Norimatsu Y, Ohmori T, Kimura A, Madoiwa S, Mimuro J, Seichi A, Yatomi Y, Hoshino Y, Sakata Y (2012) FTY720 improves functional recovery after spinal cord injury by primarily nonimmunomodulatory mechanisms. Am J Pathol 180:1625–1635

    Article  CAS  PubMed  Google Scholar 

  • Papagno C, Trojano L (2018) Cognitive and behavioral disorders in Parkinson's disease: an update. I: cognitive impairments. Neurol Sci 39:215–223

    Article  PubMed  Google Scholar 

  • Phani S, Loike JD, Przedborski S (2012) Neurodegeneration and inflammation in Parkinson's disease. Parkinsonism Relat Disord 18(Suppl 1):S207–S209

    Article  PubMed  Google Scholar 

  • Poh L, Kang SW, Baik SH, Ng GYQ, She DT, Balaganapathy P, Dheen ST, Magnus T, Gelderblom M, Sobey CG, Koo EH, Fann DY, Arumugam TV (2018) Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke. Brain Behav Immun 75:34–47. https://doi.org/10.1016/j.bbi.2018.09.001. [Epub ahead of print

    Article  CAS  PubMed  Google Scholar 

  • Rahman MM, Prunte L, Lebender LF, Patel BS, Gelissen I, Hansbro PM, Morris JC, Clark AR, Verrills NM, Ammit AJ (2016) The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells. Sci Rep 6:37297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren M, Han M, Wei X, Guo Y, Shi H, Zhang X, Perez RG, Lou H (2017) FTY720 attenuates 6-OHDA-associated dopaminergic degeneration in cellular and mouse parkinsonian models. Neurochem Res 42:686–696

    Article  CAS  PubMed  Google Scholar 

  • Rolland WN, Manaenko A, Lekic T, Hasegawa Y, Ostrowski R, Tang J, Zhang JH (2011) FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice. Acta Neurochir Suppl 111:213–217

    Article  PubMed  PubMed Central  Google Scholar 

  • Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, Ostrowski R, Manaenko A, Tang J, Zhang JH (2013) Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol 241:45–55

    Article  CAS  PubMed  Google Scholar 

  • Rutherford C, Childs S, Ohotski J, McGlynn L, Riddick M, MacFarlane S, Tasker D, Pyne S, Pyne NJ, Edwards J, Palmer TM (2013) Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1. Cell Death Dis 4:e927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkar S, Malovic E, Harishchandra DS, Ghaisas S, Panicker N, Charli A, Palanisamy BN, Rokad D, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2017) Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease. NPJ Parkinsons Dis 3:30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekine Y, Suzuki K, Remaley AT (2011) HDL and sphingosine-1-phosphate activate stat3 in prostate cancer DU145 cells via ERK1/2 and S1P receptors, and promote cell migration and invasion. Prostate 71:690–699

    Article  CAS  PubMed  Google Scholar 

  • Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15:946–950

    Article  CAS  PubMed  Google Scholar 

  • Tan B, Luo Z, Yue Y, Liu Y, Pan L, Yu L, Yin Y (2016) Effects of FTY720 (Fingolimod) on proliferation, differentiation, and migration of brain-derived neural stem cells. Stem Cells Int 2016:9671732

    PubMed  PubMed Central  Google Scholar 

  • Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194

    Article  CAS  PubMed  Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518

    Article  CAS  PubMed  Google Scholar 

  • Ugi S, Imamura T, Maegawa H, Egawa K, Yoshizaki T, Shi K, Obata T, Ebina Y, Kashiwagi A, Olefsky JM (2004) Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes. Mol Cell Biol 24:8778–8789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Horssen J, van Schaik P, Witte M (2017) Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders? Neurosci Lett

  • Velmurugan BK, Lee CH, Chiang SL, Hua CH, Chen MC, Lin SH, Yeh KT, Ko YC (2018) PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential. J Cell Physiol 233:1300–1311

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Wise RA, Baler R (2017) The dopamine motive system: implications for drug and food addiction. Nat Rev Neurosci 18:741–752

    Article  CAS  PubMed  Google Scholar 

  • Wei Y, Yemisci M, Kim HH, Yung LM, Shin HK, Hwang SK, Guo S, Qin T, Alsharif N, Brinkmann V, Liao JK, Lo EH, Waeber C (2011) Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol 69:119–129

    Article  CAS  PubMed  Google Scholar 

  • Wen L, Zhang QS, Heng Y, Chen Y, Wang S, Yuan YH, Chen NH (2018) NLRP3 inflammasome activation in the thymus of MPTP-induced parkinsonian mouse model. Toxicol Lett 288:1–8

    Article  CAS  PubMed  Google Scholar 

  • Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc Natl Acad Sci U S A 100:6145–6150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu C, Leong SY, Moore CS, Cui QL, Gris P, Bernier LP, Johnson TA, Seguela P, Kennedy TE, Bar-Or A, Antel JP (2013) Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J Neuroinflammation 10:41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin L, Bao F, Wu J, Li K (2018) NLRP3 inflammasome-dependent pyroptosis is proposed to be involved in the mechanism of age-dependent isoflurane-induced cognitive impairment. J Neuroinflammation 15:266

    Article  PubMed  PubMed Central  Google Scholar 

  • Zassler B, Schermer C, Humpel C (2003) Protein kinase C and phosphoinositol-3-kinase mediate differentiation or proliferation of slice-derived rat microglia. Pharmacology 67:211–215

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Wu Y, Xie L, Teng CH, Wu FF, Xu KB, Chen X, Xiao J, Zhang HY, Chen DQ (2018) Isoliquiritigenin protects against blood-brain barrier damage and inhibits the secretion of pro-inflammatory cytokines in mice after traumatic brain injury. Int Immunopharmacol 65:64–75

    Article  CAS  PubMed  Google Scholar 

  • Zhao P, Yang X, Yang L, Li M, Wood K, Liu Q, Zhu X (2017a) Neuroprotective effects of fingolimod in mouse models of Parkinson's disease. FASEB J 31:172–179

    Article  CAS  PubMed  Google Scholar 

  • Zhao Z, Wang R, Huo Z, Li C, Wang Z (2017b) Characterization of the anticoagulant and antithrombotic properties of the sphingosine 1-phosphate mimetic FTY720. Acta Haematol 137:1–6

    Article  CAS  PubMed  Google Scholar 

  • Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (2016YFF0101400) and the National Natural Science Foundation of China (grant number: 81571614).

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Authors and Affiliations

  1. Department of Immunology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, JS, China

    Shu Yao, Longjun Li, Xin Sun, Dongyan Shi & Hong Zhou

  2. Department of Clinical Pharmacy, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No. 1, Fuhua Road, Futian District, Shenzhen, 518033, Guangdong, China

    Jun Hua

  3. Institute of Microscope Science and Technology, Ningbo Yongxin Optics Co. Ltd., 385 Mingzhu Road, Hi-tech Industry Park, Ningbo, 315040, China

    Keqi Zhang

  4. Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    Li Hao & Lixin Liu

  5. Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, Jiangsu, China

    Hong Zhou

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  1. Shu Yao
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  2. Longjun Li
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Contributions

DYS and HZ designed and supervised the study and contributed to the drafting of the manuscript. XS, KQZ, LH, LL, DYS, and HZ wrote the manuscript. SY and LJL conceptualized and performed the experiments and contributed to the drafting of the manuscript. XS performed the experiments of primary microglia. JH assisted with behavioral testing and cell culture. JH and LJL contributed to data analysis. All authors have read and approved the final version of the manuscript.

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Correspondence to Dongyan Shi or Hong Zhou.

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Yao, S., Li, L., Sun, X. et al. FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation. J Neuroimmune Pharmacol 14, 478–492 (2019). https://doi.org/10.1007/s11481-019-09843-4

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