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

Layal Maatouk, Anne-Claire Compagnion, Maria-Angeles Carrillo- de Sauvage, Alexis-Pierre Bemelmans, Sabrina Leclere-Turbant, Vincent Cirotteau, Mira Tohme, Allen Beke, Michaël Trichet, Virginie Bazin, Bobby N. Trawick, Richard M. Ransohoff, François Tronche, Bénédicte Manoury and Sheela Vyas ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04569-y

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