title: Partial depletion of the proinflammatory monocyte population is neuroprotective in the myenteric plexus but not in the basal ganglia in a MPTP mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) patients often suffer from gastrointestinal (GI) impairments that are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric nervous system. Growing evidence suggests that inflammation originating from the gut may have a major impact in both the initiation and progression of PD. Here, we investigated the role of the innate immune response in neurodegeneration occurring in central nervous system (CNS) and enteric nervous system (ENS) in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism in both humans and animal models. We found a strong immune response in the gut of mice treated with MPTP, as demonstrated by the prominent presence of macrophages derived from CD115(+) CD11b(+) Ly6C(Hi) monocytes, known as M1 monocytes, and increased production of IL-1β and IL-6. Partial depletion of proinflammatory M1 monocytes through intravenous injections of clodronate-encapsulated liposome protects against MPTP-induced reduction of tyrosine hydroxylase (TH) expression in the ENS. In contrast, loss of striatal TH expression in the CNS after MPTP intoxication occurs regardless of partial monocyte depletion. Examination of brain tissue revealed that microglial activation, comprising the majority of the immune response in the CNS after MPTP injections is unaffected by M1 depletion. In vitro experiments revealed that MPTP and MPP(+) act directly on monocytes to elicit a proinflammatory response that is, in part, dependent on the MyD88/NF-κB signaling pathway resulting in nitrite and proinflammatory cytokine production. Taken together, our results demonstrate a critical role for proinflammatory M1 monocytes/macrophages in DAergic alterations occurring in the GI, but not in the brain, in the MPTP model of PD.
authors: Centre de recherche du CHU de Québec, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.
authors: M
authors: M
authors: Côté
authors: Centre de recherche du CHU de Québec, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.
authors: A-A
authors: AA
authors: Poirier
authors: Centre de recherche du CHU de Québec, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.
authors: B
authors: B
authors: Aubé
authors: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, FL, USA.
authors: C
authors: C
authors: Jobin
authors: Centre de recherche du CHU de Québec, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Faculté de médecine, Département de Médecine Moléculaire, Université Laval, Québec, QC G1K 0A6, Canada.
authors: S
authors: S
authors: Lacroix
authors: Centre de recherche du CHU de Québec, Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Faculté de médecine, Département de Psychiatrie et Neurosciences, Université Laval, Québec, QC G1K 0A6, Canada. Electronic address: denis.soulet@crchul.ulaval.ca.
authors: D
authors: D
authors: Soulet
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D009197:Myenteric Plexus / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6
keywords: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Central nervous system; Enteric nervous system; Inflammation; Macrophage; Microglia; Parkinson’s disease; Tyrosine hydroxylase