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Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation

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Abstract

Parkin is an E3 ubiquitin ligase involved in Parkinson’s disease (PD). Necroptosis is a regulated form of cell death that depends on receptor interacting protein 1 (RIP1) and 3 (RIP3). Importantly, parkin has been implicated in ubiquitination events that can alter inflammation and necroptosis. Here, we investigated how parkin influences microglial function. Incubation of BV-2 microglial cells with zVAD.fmk (zVAD) induced high levels of cell death and viability loss, while N9 microglial cells and primary microglia required further stimuli. Importantly, necrostatin-1 (Nec-1), an inhibitor of RIP1 kinase activity, abrogated cell death, thus implicating RIP1-dependent necroptosis in cell death. Cell death was characterized by necrosome assembly, as determined by sequestration of RIP1/RIP3 in insoluble fractions and by MLKL phosphorylation, which were all abolished by Nec-1. Also, necroptosis-inducing conditions led to TNF-α secretion, which may in turn contribute to autocrine necroptosis activation. Interestingly, parkin knockdown protected BV-2 cells from zVAD-induced necroptosis, which may depend on the higher RIP1 ubiquitination levels detected in siRNA-PARK2 transfected cells. This effect was independent of inflammation, since pro-inflammatory stimulation of BV-2 and primary microglia with silenced parkin resulted in stronger pro-inflammatory gene expression, an opposite observation from zVAD-exposed BV-2 cells. LPS-mediated inflammation was exacerbated by NF-κB/JNK over-activation. Finally, no alterations in mitochondrial ROS production were detected in any condition, thereby excluding the role of parkin in mitophagy. In conclusion, here, we reveal that parkin may have unsuspected roles in microglia by modulating ubiquitination. Parkin loss exacerbates inflammation and promotes survival of activated microglia, thus contributing to chronic neuroinflammation.

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References

  1. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. https://doi.org/10.1038/nrdp.2017.13

    Article  PubMed  Google Scholar 

  2. Henn IH, Gostner JM, Lackner P, Tatzelt J, Winklhofer KF (2005) Pathogenic mutations inactivate parkin by distinct mechanisms. J Neurochem 92(1):114–122. https://doi.org/10.1111/j.1471-4159.2004.02854.x

    Article  CAS  PubMed  Google Scholar 

  3. Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE (2007) Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 6(7):652–662. https://doi.org/10.1016/S1474-4422(07)70174-6

    Article  CAS  PubMed  Google Scholar 

  4. Dawson TM, Dawson VL (2010) The role of parkin in familial and sporadic Parkinson’s disease. Mov Disord 25(Suppl 1):S32–S39. https://doi.org/10.1002/mds.22798

    Article  PubMed  PubMed Central  Google Scholar 

  5. Seirafi M, Kozlov G, Gehring K (2015) Parkin structure and function. FEBS J 282(11):2076–2088. https://doi.org/10.1111/febs.13249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Muller-Rischart AK, Pilsl A, Beaudette P et al (2013) The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. Mol Cell 49(5):908–921. https://doi.org/10.1016/j.molcel.2013.01.036

    Article  CAS  PubMed  Google Scholar 

  7. Henn IH, Bouman L, Schlehe JS, Schlierf A, Schramm JE, Wegener E, Nakaso K, Culmsee C et al (2007) Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci 27(8):1868–1878. https://doi.org/10.1523/JNEUROSCI.5537-06.2007

    Article  CAS  PubMed  Google Scholar 

  8. Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS et al (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501(7468):512–516. https://doi.org/10.1038/nature12566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. de Leseleuc L, Orlova M, Cobat A et al (2013) PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. PLoS Negl Trop Dis 7(1):e2015. https://doi.org/10.1371/journal.pntd.0002015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Letsiou E, Sammani S, Wang H, Belvitch P, Dudek SM (2017) Parkin regulates lipopolysaccharide-induced proinflammatory responses in acute lung injury. Transl Res 181:71–82. https://doi.org/10.1016/j.trsl.2016.09.002

    Article  CAS  PubMed  Google Scholar 

  11. Tran TA, Nguyen AD, Chang J, Goldberg MS, Lee JK, Tansey MG (2011) Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B. PLoS One 6(8):e23660. https://doi.org/10.1371/journal.pone.0023660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chung JY, Park HR, Lee SJ, Lee SH, Kim JS, Jung YS, Hwang SH, Ha NC et al (2013) Elevated TRAF2/6 expression in Parkinson’s disease is caused by the loss of Parkin E3 ligase activity. Lab Investig 93(6):663–676. https://doi.org/10.1038/labinvest.2013.60

    Article  CAS  PubMed  Google Scholar 

  13. Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J et al (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36(5):831–844. https://doi.org/10.1016/j.molcel.2009.10.013

    Article  CAS  PubMed  Google Scholar 

  14. Ofengeim D, Yuan J (2013) Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 14(11):727–736. https://doi.org/10.1038/nrm3683

    Article  CAS  PubMed  Google Scholar 

  15. Kearney CJ, Martin SJ (2017) An inflammatory perspective on necroptosis. Mol Cell 65(6):965–973. https://doi.org/10.1016/j.molcel.2017.02.024

    Article  CAS  PubMed  Google Scholar 

  16. Kim SJ, Li J (2013) Caspase blockade induces RIP3-mediated programmed necrosis in toll-like receptor-activated microglia. Cell Death Dis 4:e716. https://doi.org/10.1038/cddis.2013.238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu X, Shi F, Li Y, Yu X, Peng S, Li W, Luo X, Cao Y (2016) Post-translational modifications as key regulators of TNF-induced necroptosis. Cell Death Dis 7(7):e2293. https://doi.org/10.1038/cddis.2016.197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D et al (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150(2):339–350. https://doi.org/10.1016/j.cell.2012.06.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS et al (2014) Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell 54(1):133–146. https://doi.org/10.1016/j.molcel.2014.03.003

    Article  CAS  PubMed  Google Scholar 

  20. Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, Readhead B, Dudley JT et al (2017) Necroptosis activation in Alzheimer’s disease. Nat Neurosci 20(9):1236–1246. https://doi.org/10.1038/nn.4608

    Article  CAS  PubMed  Google Scholar 

  21. Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, Massimino L, Rubio A et al (2018) Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Rep 22(8):2066–2079. https://doi.org/10.1016/j.celrep.2018.01.089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27(2–3):229–237

    Article  CAS  Google Scholar 

  23. Righi M, Mori L, De Libero G et al (1989) Monokine production by microglial cell clones. Eur J Immunol 19(8):1443–1448. https://doi.org/10.1002/eji.1830190815

    Article  CAS  PubMed  Google Scholar 

  24. Nikodemova M, Watters JJ (2011) Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice. Neuroscience 190:67–74. https://doi.org/10.1016/j.neuroscience.2011.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gordo AC, Falcao AS, Fernandes A, Brito MA, Silva RF, Brites D (2006) Unconjugated bilirubin activates and damages microglia. J Neurosci Res 84(1):194–201. https://doi.org/10.1002/jnr.20857

    Article  CAS  PubMed  Google Scholar 

  26. Saura J, Tusell JM, Serratosa J (2003) High-yield isolation of murine microglia by mild trypsinization. Glia 44(3):183–189. https://doi.org/10.1002/glia.10274

    Article  PubMed  Google Scholar 

  27. Witting A, Moller T (2011) Microglia cell culture: a primer for the novice. Methods Mol Biol 758:49–66. https://doi.org/10.1007/978-1-61779-170-3_4

    Article  CAS  PubMed  Google Scholar 

  28. Pereira DM, Simoes AE, Gomes SE et al (2016) MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism. Oncotarget 7(23):34322–34340. https://doi.org/10.18632/oncotarget.9107

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488(7412):499–503. https://doi.org/10.1038/nature11280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fricker M, Vilalta A, Tolkovsky AM, Brown GC (2013) Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J Biol Chem 288(13):9145–9152. https://doi.org/10.1074/jbc.M112.427880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tait SW, Oberst A, Quarato G et al (2013) Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep 5(4):878–885. https://doi.org/10.1016/j.celrep.2013.10.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bernas T, Dobrucki J (2002) Mitochondrial and nonmitochondrial reduction of MTT: Interaction of MTT with TMRE, JC-1, and NAO mitochondrial fluorescent probes. Cytometry 47(4):236–242

    Article  CAS  Google Scholar 

  33. Wu YT, Tan HL, Huang Q, Sun XJ, Zhu X, Shen HM (2011) zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFalpha mediated by the PKC-MAPKs-AP-1 pathway. Cell Death Differ 18(1):26–37. https://doi.org/10.1038/cdd.2010.72

    Article  CAS  PubMed  Google Scholar 

  34. Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman C, Zhu H, Gerber SA, Gygi S et al (2012) A novel role for RIP1 kinase in mediating TNFalpha production. Cell Death Dis 3:e320. https://doi.org/10.1038/cddis.2012.64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kerksick C, Willoughby D (2005) The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr 2:38–44. https://doi.org/10.1186/1550-2783-2-2-38

    Article  PubMed  PubMed Central  Google Scholar 

  36. Afonso MB, Rodrigues PM, Carvalho T, Caridade M, Borralho P, Cortez-Pinto H, Castro RE, Rodrigues CMP (2015) Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. Clin Sci (Lond) 129(8):721–739. https://doi.org/10.1042/CS20140732

    Article  CAS  Google Scholar 

  37. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA et al (2011) Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471(7340):591–596. https://doi.org/10.1038/nature09816

    Article  CAS  PubMed  Google Scholar 

  38. de Almagro MC, Goncharov T, Newton K, Vucic D (2015) Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. Cell Death Dis 6:e1800. https://doi.org/10.1038/cddis.2015.158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors. Nat Immunol 11(5):373–384. https://doi.org/10.1038/ni.1863

    Article  CAS  PubMed  Google Scholar 

  40. Wang MJ, Huang HY, Chen WF, Chang HF, Kuo JS (2010) Glycogen synthase kinase-3beta inactivation inhibits tumor necrosis factor-alpha production in microglia by modulating nuclear factor kappaB and MLK3/JNK signaling cascades. J Neuroinflammation 7:99. https://doi.org/10.1186/1742-2094-7-99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu K, Liang W, Ma Z, Xu D, Cao S, Lu X, Liu N, Shan B et al (2018) Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression. Cell Death Dis 9(5):500. https://doi.org/10.1038/s41419-018-0524-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li Z, Scott MJ, Fan EK, Li Y, Liu J, Xiao G, Li S, Billiar TR et al (2016) Tissue damage negatively regulates LPS-induced macrophage necroptosis. Cell Death Differ 23(9):1428–1447. https://doi.org/10.1038/cdd.2016.21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. McComb S, Cheung HH, Korneluk RG, Wang S, Krishnan L, Sad S (2012) cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation. Cell Death Differ 19(11):1791–1801. https://doi.org/10.1038/cdd.2012.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Voloboueva LA, Emery JF, Sun X, Giffard RG (2013) Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett 587(6):756–762. https://doi.org/10.1016/j.febslet.2013.01.067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Park J, Choi H, Min JS, Park SJ, Kim JH, Park HJ, Kim B, Chae JI et al (2013) Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells. J Neurochem 127(2):221–232. https://doi.org/10.1111/jnc.12361

    Article  CAS  PubMed  Google Scholar 

  46. Bordt EA, Polster BM (2014) NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair? Free Radic Biol Med 76:34–46. https://doi.org/10.1016/j.freeradbiomed.2014.07.033

    Article  CAS  PubMed  Google Scholar 

  47. Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA (2005) Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation. J Biol Chem 280(44):36560–36566. https://doi.org/10.1074/jbc.M506831200

    Article  CAS  PubMed  Google Scholar 

  48. De Boer ML, Hu J, Kalvakolanu DV, Hasday JD, Cross AS (2001) IFN-gamma inhibits lipopolysaccharide-induced interleukin-1 beta in primary murine macrophages via a Stat1-dependent pathway. J Interf Cytokine Res 21(7):485–494. https://doi.org/10.1089/10799900152434358

    Article  Google Scholar 

  49. Ucla C, Roux-Lombard P, Fey S, Dayer JM, Mach B (1990) Interferon gamma drastically modifies the regulation of interleukin 1 genes by endotoxin in U937 cells. J Clin Invest 85(1):185–191. https://doi.org/10.1172/JCI114411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M, Kitada T, Glass K, Owen CA et al (2014) Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest 124(9):3987–4003. https://doi.org/10.1172/JCI74985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Basit F, van Oppen LM, Schockel L et al (2017) Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis 8(3):e2716. https://doi.org/10.1038/cddis.2017.133

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhang Y, Su SS, Zhao S, Yang Z, Zhong CQ, Chen X, Cai Q, Yang ZH et al (2017) RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat Commun 8:14329. https://doi.org/10.1038/ncomms14329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schenk B, Fulda S (2015) Reactive oxygen species regulate Smac mimetic/TNFalpha-induced necroptotic signaling and cell death. Oncogene 34(47):5796–5806. https://doi.org/10.1038/onc.2015.35

    Article  CAS  PubMed  Google Scholar 

  54. Yang Z, Wang Y, Zhang Y, He X, Zhong CQ, Ni H, Chen X, Liang Y et al (2018) RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis. Nat Cell Biol 20(2):186–197. https://doi.org/10.1038/s41556-017-0022-y

    Article  CAS  PubMed  Google Scholar 

  55. Remijsen Q, Goossens V, Grootjans S, van den Haute C, Vanlangenakker N, Dondelinger Y, Roelandt R, Bruggeman I et al (2014) Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis 5:e1004. https://doi.org/10.1038/cddis.2013.531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X et al (2015) Activation of necroptosis in multiple sclerosis. Cell Rep 10(11):1836–1849. https://doi.org/10.1016/j.celrep.2015.02.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kearney CJ, Cullen SP, Tynan GA, Henry CM, Clancy D, Lavelle EC, Martin SJ (2015) Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production. Cell Death Differ 22(8):1313–1327. https://doi.org/10.1038/cdd.2014.222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cha GH, Kim S, Park J, Lee E, Kim M, Lee SB, Kim JM, Chung J et al (2005) Parkin negatively regulates JNK pathway in the dopaminergic neurons of drosophila. Proc Natl Acad Sci U S A 102(29):10345–10350. https://doi.org/10.1073/pnas.0500346102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ren Y, Jiang H, Yang F, Nakaso K, Feng J (2009) Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J Biol Chem 284(6):4009–4017. https://doi.org/10.1074/jbc.M806245200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu M, Aneja R, Sun X, Xie S, Wang H, Wu X, Dong JT, Li M et al (2008) Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase. J Biol Chem 283(51):35783–35788. https://doi.org/10.1074/jbc.M806860200

    Article  CAS  PubMed  Google Scholar 

  61. Jiang H, Ren Y, Zhao J, Feng J (2004) Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet 13(16):1745–1754. https://doi.org/10.1093/hmg/ddh180

    Article  CAS  PubMed  Google Scholar 

  62. Shen HM, Liu ZG (2006) JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic Biol Med 40(6):928–939. https://doi.org/10.1016/j.freeradbiomed.2005.10.056

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) through iMed.ULisboa grant UID/DTP/04138/2013 and individual fellowships SFRH/BPD/100961/2014, PD/BD/128332/2017 and SFRH/BD/102771/2014.

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  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal

    Pedro Elói Antunes Dionísio, Sara Rodrigues Oliveira, Joana São José Dias Amaral & Cecília Maria Pereira Rodrigues

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Dionísio, P.A., Oliveira, S.R., Amaral, J.D. et al. Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation. Mol Neurobiol 56, 2990–3004 (2019). https://doi.org/10.1007/s12035-018-1264-9

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