title: Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism.
abstract: Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7224, F-75005 Paris, France.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ros-Bernal
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hunot
authors.forename: Maria Trinidad
authors.initials: MT
authors.lastname: Herrero
authors.forename: Sebastien
authors.initials: S
authors.lastname: Parnadeau
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Lixia
authors.initials: L
authors.lastname: Lu
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Fischer
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Carrillo-de Sauvage
authors.forename: Françoise
authors.initials: F
authors.lastname: Saurini
authors.forename: Christiane
authors.initials: C
authors.lastname: Coussieu
authors.forename: Kiyoka
authors.initials: K
authors.lastname: Kinugawa
authors.forename: Annick
authors.initials: A
authors.lastname: Prigent
authors.forename: Günter
authors.initials: G
authors.lastname: Höglinger
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Sheela
authors.initials: S
authors.lastname: Vyas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D011965:Receptors, Glucocorticoid; D051193:Toll-Like Receptors