Archives of Toxicology

, Volume 91, Issue 1, pp 231–246 | Cite as

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

  • Liudmila Efremova
  • Petra Chovancova
  • Martina Adam
  • Simon Gutbier
  • Stefan Schildknecht
  • Marcel LeistEmail author
Molecular Toxicology


Astrocytes, the largest cell population in the human brain, are powerful inflammatory effectors. Several studies have examined the interaction of activated astrocytes with neurons, but little is known yet about human neurotoxicity under such situations and about strategies of neuronal rescue. To address this question, immortalized murine astrocytes (IMA) were combined with human LUHMES neurons and stimulated with an inflammatory (TNF, IL-1) cytokine mix (CM). Neurotoxicity was studied both in co-cultures and in monocultures after transfer of conditioned medium from activated IMA. Interventions with >20 drugs were used to profile the model system. Control IMA supported neurons and protected them from neurotoxicants. Inflammatory activation reduced this protection, and prolonged exposure of co-cultures to CM triggered neurotoxicity. Neither the added cytokines nor the release of NO from astrocytes were involved in this neurodegeneration. The neurotoxicity-mediating effect of IMA was faithfully reproduced by human astrocytes. Moreover, glia-dependent toxicity was also observed, when IMA cultures were stimulated with CM, and the culture medium was transferred to neurons. Such neurotoxicity was prevented when astrocytes were treated by p38 kinase inhibitors or dexamethasone, whereas such compounds had no effect when added to neurons. Conversely, treatment of neurons with five different drugs, including resveratrol and CEP1347, prevented toxicity of astrocyte supernatants. Thus, the sequential IMA-LUHMES neuroinflammation model is suitable for separate profiling of both glial-directed and directly neuroprotective strategies. Moreover, direct evaluation in co-cultures of the same cells allows for testing of therapeutic effectiveness in more complex settings, in which astrocytes affect pharmacological properties of neurons.


LUHMES Astrocyte p38 kinase Neuroinflammation Neuropharmacology 



Parkinson’s disease










Glial-derived neurotrophic factor


Immortalized mouse astrocytes


Lactate dehydrogenase


5,5′-Dithiobis(2-nitrobenzoic acid)




l-Glutathione oxidized






Rho kinase


Differentiation medium


Dopamine transporter


Lund human mesencephalic cells


Tumor necrosis factor alpha


Interleukin-1 beta


Interferon gamma


Cytokine mix


Complete cytokine mix




Central nerve system


Vesicular monoamine transporter


Tyrosine hydroxylase


Normal human astrocytes


Nuclear factor kappa-light-chain-enhancer of activated B cells


NF-kappa-B inhibitor beta




Nitric oxide synthase


Cyclic adenosine monophosphate


Neuroepithelial cells


Mouse astrocytes generated from embryonic stem cells


Substantia nigra pars compacta




Neuron-specific enolase



This work was supported by the Doerenkamp-Zbinden Foundation, the Land BW, the DFG (RTG1331; KoRS-CB), the BMBF, and University of Konstanz funds.

Author’s contribution

Liudmila Efremova and Petra Chovancova performed most experiments, analyzed data, and wrote the manuscript; Stefan Schildknecht, Martina Adam, and Simon Gutbier performed experiments and proofread the manuscript; Marcel Leist designed experiments and wrote the manuscript.

Supplementary material

204_2016_1702_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1163 kb)


  1. Allen NJ, Barres BA (2009) Glia—more than just brain glue. Nature 457:675–677CrossRefPubMedGoogle Scholar
  2. Avendano BC, Montero TD, Chavez CE, von Bernhardi R, Orellana JA (2015) Prenatal exposure to inflammatory conditions increases Cx43 and Panx1 unopposed channel opening and activation of astrocytes in the offspring effect on neuronal survival. Glia 63(11):2058–2072CrossRefGoogle Scholar
  3. Bal-Price A, Brown GC (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci Off J Soc Neurosci 21(17):6480–6491Google Scholar
  4. Bal-Price A, Moneer Z, Brown GC (2002) Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. Glia 40(3):312–323CrossRefPubMedGoogle Scholar
  5. Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q et al (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci USA 110:4069–4074CrossRefPubMedPubMedCentralGoogle Scholar
  6. Biber K, Owens T, Boddeke E (2014) What is microglia neurotoxicity (not)? Glia 62:841–854CrossRefPubMedGoogle Scholar
  7. Biesmans S, Acton PD, Cotto C, Langlois X, Ver Donck L, Bouwknecht JA et al (2015) Effect of stress and peripheral immune activation on astrocyte activation in transgenic bioluminescent Gfap-luc mice. Glia 63:1126–1137CrossRefPubMedGoogle Scholar
  8. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69CrossRefPubMedGoogle Scholar
  9. Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R et al (2014) Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci 34:8546–8556CrossRefPubMedGoogle Scholar
  10. Brown GC, Neher JJ (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 41:242–247CrossRefPubMedGoogle Scholar
  11. Buffo A, Rolando C, Ceruti S (2010) Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 79:77–89CrossRefPubMedGoogle Scholar
  12. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278CrossRefPubMedGoogle Scholar
  13. Carbone M, Duty S, Rattray M (2012) Riluzole neuroprotection in a Parkinson’s disease model involves suppression of reactive astrocytosis but not GLT-1 regulation. BMC Neurosci 13:38CrossRefPubMedPubMedCentralGoogle Scholar
  14. Castillo J, Dávalos A, Alvarez-Sabín J, Pumar JM, Leira R et al (2002) Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58:624–629CrossRefPubMedGoogle Scholar
  15. Chen Y, Vartiainen NE, Ying W, Chan PH, Koistinaho J, Swanson RA (2001) Astrocytes protect neurons from nitric oxide toxicity by a glutathione-dependent mechanism. J Neurochem 77:1601–1610CrossRefPubMedGoogle Scholar
  16. Cipriani S, Desjardins CA, Burdett TC, Xu Y, Xu K, Schwarzschild MA (2012) Protection of dopaminergic cells by urate requires its accumulation in astrocytes. J Neurochem 123:172–181CrossRefPubMedPubMedCentralGoogle Scholar
  17. Dodla MC, Mumaw J, Stice SL (2010) Role of astrocytes, soluble factors, cells adhesion molecules and neurotrophins in functional synapse formation: implications for human embryonic stem cell derived neurons. Curr Stem Cell Res Ther 5:251–260CrossRefPubMedGoogle Scholar
  18. Efremova L, Schildknecht S, Adam M, Pape R, Gutbier S, Hanf B et al (2015) Prevention of human dopaminergic neurodegeneration in an astrocytes co-culture system allowing endogenous drug metabolism. Br J Pharmacol 172:4119–4132CrossRefPubMedPubMedCentralGoogle Scholar
  19. Falsig J, Latta M, Leist M (2004a) Defined inflammatory states in astrocyte cultures: correlation with susceptibility towards CD95-driven apoptosis. J Neurochem 88:181–193CrossRefPubMedGoogle Scholar
  20. Falsig J, Porzgen P, Lotharius J, Leist M (2004b) Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. J Immunol 173:2762–2770CrossRefPubMedGoogle Scholar
  21. Falsig J, Porzgen P, Lund S, Schrattenholz A, Leist M (2006) The inflammatory transcriptome of reactive murine astrocytes and implications for their innate immune function. J Neurochem 96:893–907CrossRefPubMedGoogle Scholar
  22. Falsig J, van Beek J, Hermann C, Leist M (2008) Molecular basis for detection of invading pathogens in the brain. J Neurosci Res 86:1434–1447CrossRefPubMedGoogle Scholar
  23. Forno LS, DeLanney LE, Irwin I, Di Monte D, Langston JW (1992) Astrocytes and Parkinson’s disease. Prog Brain Res 94:429–436CrossRefPubMedGoogle Scholar
  24. Gallardo G, Barowski J, Ravits J, Siddique T, Lingrel JB, Robertson J et al (2014) An alpha2-Na/K ATPase/alpha-adducin complex in astrocytes triggers non-cell autonomous neurodegeneration. Nat Neurosci 17:1710–1719CrossRefPubMedPubMedCentralGoogle Scholar
  25. Gandelman M, Peluffo H, Beckman JS, Cassina P, Barbeito L (2010) Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis. J Neuroinflammation 7:33CrossRefPubMedPubMedCentralGoogle Scholar
  26. Gantner F, Leist M, Kusters S, Vogt K, Volk HD, Tiegs G (1996) T cell stimulus-induced crosstalk between lymphocytes and liver macrophages results in augmented cytokine release. Exp Cell Res 229:137–146CrossRefPubMedGoogle Scholar
  27. Gao X, Chen H, Schwarzschild MA, Ascherio A (2011) Use of ibuprofen and risk of Parkinson disease. Neurology 76:863–869CrossRefPubMedPubMedCentralGoogle Scholar
  28. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011) Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2:e167CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gegg ME, Clark JB (1036) Heales, SJ (2005) Co-culture of neurones with glutathione deficient astrocytes leads to increased neuronal susceptibility to nitric oxide and increased glutamate-cysteine ligase activity. Brain Res 1–2:1–6Google Scholar
  30. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551CrossRefPubMedGoogle Scholar
  31. Guizzetti M, Moore NH, Giordano G, Costa LG (2008) Modulation of neuritogenesis by astrocyte muscarinic receptors. J Biol Chem 283:31884–31897CrossRefPubMedPubMedCentralGoogle Scholar
  32. Gupta K, Patani R, Baxter P, Serio A, Story D, Tsujita T et al (2012) Human embryonic stem cell derived astrocytes mediate non-cell-autonomous neuroprotection through endogenous and drug-induced mechanisms. Cell Death Differ 19:779–787CrossRefPubMedGoogle Scholar
  33. Hansson O, Castilho RF, Kaminski Schierle GS, Karlsson J, Nicotera P, Leist M et al (2000) Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons. Exp Neurol 164:102–111CrossRefPubMedGoogle Scholar
  34. Hashioka S, McGeer EG, Miyaoka T, Wake R, Horiguchi J, McGeer PL (2015) Interferon-gamma-induced neurotoxicity of human astrocytes. CNS Neurol Disord: Drug Targets 14(2):251–256CrossRefGoogle Scholar
  35. Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7):463–477CrossRefPubMedGoogle Scholar
  36. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405CrossRefPubMedGoogle Scholar
  37. Henn A, Kirner S, Leist M (2011) TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes. J Immunol 186:3237–3247CrossRefPubMedGoogle Scholar
  38. Hunter RL, Cheng B, Choi DY, Liu M, Liu S, Cass WA et al (2009) Intrastriatal lipopolysaccharide injection induces parkinsonism in C57/B6 mice. J Neurosci Res 87:1913–1921CrossRefPubMedPubMedCentralGoogle Scholar
  39. In’T Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T et al (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345:1515–1521CrossRefGoogle Scholar
  40. Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I, Czlonkowski A, Czlonkowska A (1998) Microglial and astrocytic involvement in a murine model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 39:167–180CrossRefPubMedGoogle Scholar
  41. Krug AK, Gutbier S, Zhao L, Poltl D, Kullmann C, Ivanova V et al (2014) Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). Cell Death Dis 5:e1222CrossRefPubMedPubMedCentralGoogle Scholar
  42. Kuegler PB, Baumann BA, Zimmer B, Keller S, Marx A, Kadereit S et al (2012) GFAP-independent inflammatory competence and trophic functions of astrocytes generated from murine embryonic stem cells. Glia 60:218–228CrossRefPubMedGoogle Scholar
  43. Kurkowska-Jastrzebska I, Litwin T, Joniec I, Ciesielska A, Przybylkowski A, Czlonkowski A et al (2004) Dexamethasone protects against dopaminergic neurons damage in a mouse model of Parkinson’s disease. Int Immunopharmacol 4:1307–1318CrossRefPubMedGoogle Scholar
  44. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL (2010) Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24(7):2533–2545CrossRefPubMedGoogle Scholar
  45. Lee M, McGeer E, Kodela R, Kashfi K, McGeer PL (2013a) NOSH-aspirin (NBS-1120), a novel nitric oxide and hydrogen sulfide releasing hybrid, attenuates neuroinflammation induced by microglial and astrocytic activation: a new candidate for treatment of neurodegenerative disorders. Glia 61(10):1724–1734CrossRefPubMedGoogle Scholar
  46. Lee M, McGeer E, McGeer PL (2013b) Neurotoxins released from interferon-gamma-stimulated human astrocytes. Neuroscience 229:164–175CrossRefPubMedGoogle Scholar
  47. Lindholm P, Voutilainen MH, Lauren J, Peranen J, Leppanen VM, Andressoo JO et al (2007) Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 448:73–77CrossRefPubMedGoogle Scholar
  48. Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK et al (2011) A role for glia in the progression of Rett’s syndrome. Nature 475:497–500CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lukovic D, Stojkovic M, Moreno-Manzano V, Jendelova P, Sykova E, Bhattacharya SS et al (2015) Concise review: reactive astrocytes and stem cells in spinal cord injury: good guys or bad guys? Stem Cells 33:1036–1041CrossRefPubMedGoogle Scholar
  50. Ma D, Jin S, Li E, Doi Y, Parajuli B, Noda M et al (2013) The neurotoxic effect of astrocytes activated with toll-like receptor ligands. J Neuroimmunol 254:10–18CrossRefPubMedGoogle Scholar
  51. Mander P, Borutaite V, Moncada S, Brown GC (2005) Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. J Neurosci Res 79(1–2):208–215CrossRefPubMedGoogle Scholar
  52. Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689CrossRefPubMedGoogle Scholar
  53. Mattson MP, Barger SW, Furukawa K, Bruce AJ, Wyss-Coray T, Mark RJ et al (1997) Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer’s disease. Brain Res Brain Res Rev 23:47–61CrossRefPubMedGoogle Scholar
  54. Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI et al (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20:1147–1156CrossRefPubMedPubMedCentralGoogle Scholar
  55. Medeiros R, LaFerla FM (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239:133–138CrossRefPubMedGoogle Scholar
  56. Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622CrossRefPubMedPubMedCentralGoogle Scholar
  57. Orre M, Kamphuis W, Osborn LM, Jansen AH, Kooijman L, Bossers K et al (2014) Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging 35:2746–2760CrossRefPubMedGoogle Scholar
  58. Pekny M, Wilhelmsson U, Bogestal YR, Pekna M (2007) The role of astrocytes and complement system in neural plasticity. Int Rev Neurobiol 82:95–111CrossRefPubMedGoogle Scholar
  59. Pizzurro DM, Dao K, Costa LG (2014) Astrocytes protect against diazinon- and diazoxon-induced inhibition of neurite outgrowth by regulating neuronal glutathione. Toxicology 318:59–68CrossRefPubMedPubMedCentralGoogle Scholar
  60. Puschmann TB, Zanden C, De Pablo Y, Kirchhoff F, Pekna M, Liu J et al (2013) Bioactive 3D cell culture system minimizes cellular stress and maintains the in vivo-like morphological complexity of astroglial cells. Glia 61:432–440CrossRefPubMedGoogle Scholar
  61. Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE et al (2011) Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD008454 PubMedCentralGoogle Scholar
  62. Robel S, Berninger B, Gotz M (2011) The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci 12:88–104CrossRefPubMedGoogle Scholar
  63. Ruitenberg A, Kalmijn S, de Ridder MA, Redekop WK, van Harskamp F, Hofman A et al (2001) Prognosis of Alzheimer’s disease: the Rotterdam Study. Neuroepidemiology 20:188–195CrossRefPubMedGoogle Scholar
  64. Sandstrom von Tobel J, Zoia D, Althaus J, Antinori P, Mermoud J, Pak HS et al (2014) Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures. Toxicol Lett 230:188–197CrossRefPubMedGoogle Scholar
  65. Schildknecht S, Kirner S, Henn A, Gasparic K, Pape R, Efremova L et al (2012) Characterization of mouse cell line IMA 2.1 as a potential model system to study astrocyte functions. Altex Altern Anim Exp 29:261–274Google Scholar
  66. Scholz D, Poltl D, Genewsky A, Weng M, Waldmann T, Schildknecht S et al (2011) Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. J Neurochem 119:957–971CrossRefPubMedGoogle Scholar
  67. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H et al (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406PubMedGoogle Scholar
  68. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156CrossRefPubMedGoogle Scholar
  69. Simon BM, Malisan F, Testi R, Nicotera P, Leist M (2002) Disialoganglioside GD3 is released by microglia and induces oligodendrocyte apoptosis. Cell Death Differ 9:758–767CrossRefPubMedGoogle Scholar
  70. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35CrossRefPubMedGoogle Scholar
  71. Valenza M, Marullo M, Di Paolo E, Cesana E, Zuccato C, Biella G et al (2015) Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease. Cell Death Differ 22:690–702CrossRefPubMedGoogle Scholar
  72. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640CrossRefPubMedGoogle Scholar
  73. Walker DG, Kim SU, McGeer PL (1998) Expression of complement C4 and C9 genes by human astrocytes. Brain Res 809(1):31–38CrossRefPubMedGoogle Scholar
  74. Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A et al (2012) Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 287:21384–21395CrossRefPubMedPubMedCentralGoogle Scholar
  75. Ward RJ, Colivicchi MA, Allen R, Schol F, Lallemand F, de Witte P, Ballini C et al (2009) Neuro-inflammation induced in the hippocampus of ‘binge drinking’ rats may be mediated by elevated extracellular glutamate content. J Neurochem 111:1119–1128CrossRefPubMedGoogle Scholar
  76. Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q et al (2014) Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum Mol Genet 23:2968–2980CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Liudmila Efremova
    • 1
    • 2
  • Petra Chovancova
    • 1
    • 3
  • Martina Adam
    • 1
  • Simon Gutbier
    • 1
    • 2
  • Stefan Schildknecht
    • 1
  • Marcel Leist
    • 1
    Email author
  1. 1.Doerenkamp-Zbinden Chair for In Vitro Toxicology and BiomedicineUniversity of KonstanzConstanceGermany
  2. 2.Research Training Group 1331 (RTG1331)University of KonstanzConstanceGermany
  3. 3.Konstanz Research School Chemical BiologyUniversity of KonstanzConstanceGermany

Personalised recommendations