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TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons

Author

Listed:
  • Layal Maatouk

    (Sorbonne Université, CNRS UMR 8246 & INSERM U1130)

  • Anne-Claire Compagnion

    (Sorbonne Université, CNRS UMR 8246 & INSERM U1130)

  • Maria-Angeles Carrillo-de Sauvage

    (Université Paris-Sud, Université Paris-Saclay (UMR9199))

  • Alexis-Pierre Bemelmans

    (Université Paris-Sud, Université Paris-Saclay (UMR9199))

  • Sabrina Leclere-Turbant

    (Hôpital de la Pitié-Salpétrière)

  • Vincent Cirotteau

    (Sorbonne Université, CNRS UMR 8246 & INSERM U1130)

  • Mira Tohme

    (Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine)

  • Allen Beke

    (Sorbonne Université, CNRS UMR 8246 & INSERM U1130)

  • Michaël Trichet

    (Sorbonne Université FR3631)

  • Virginie Bazin

    (Sorbonne Université FR3631)

  • Bobby N. Trawick

    (Mallinckrodt Pharmaceuticals)

  • Richard M. Ransohoff

    (Third Rock Ventures)

  • François Tronche

    (Sorbonne Université, CNRS UMR 8246 & INSERM U1130)

  • Bénédicte Manoury

    (Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine)

  • Sheela Vyas

    (Sorbonne Université, CNRS UMR 8246 & INSERM U1130)

Abstract

Inflammation is a characteristic feature of Parkinson’s disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls. TLR9 deletion reduced DN loss in neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. GR regulates TLR9 activation during MPTP neurotoxicity as TLR9 antagonist suppressed increased DN loss in microglia/macrophage GR mutant mice. GR absence in microglia enhanced TLR9 translocation to endolysosomes and facilitated its cleavage leading to pro-inflammatory gene expression. GR-dependent TLR9 activation also triggered DN loss following intranigral injection of mitochondrial DNA. Finally, microglial GR sensitivity to A53T-alpha-synuclein induced DN degeneration as well as decreased microglial GR expression observed in SN of PD brain samples, all suggest that reduced microglial GR activity in SN can stimulate TLR9 activation and DN loss in PD pathology.

Suggested Citation

  • Layal Maatouk & Anne-Claire Compagnion & Maria-Angeles Carrillo-de Sauvage & Alexis-Pierre Bemelmans & Sabrina Leclere-Turbant & Vincent Cirotteau & Mira Tohme & Allen Beke & Michaël Trichet & Virgini, 2018. "TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04569-y
    DOI: 10.1038/s41467-018-04569-y
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