title: GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease.
abstract: Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17β-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-κB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory "M2" immunophenotype reducing MPP(+)-induced NF-κB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies.
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada; Faculty of Medicine, Department of Psychiatry and Neuroscience, Laval University, Quebec City, Quebec, Canada.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Côté
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
authors.forename: Andrée-Anne
authors.initials: AA
authors.lastname: Poirier
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Aubé
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
authors.affiliation: Axe Neurosciences, Centre de Recherche du CHU de Québec (Pavilion CHUL), Quebec, Canada; Faculty of Medicine, Department of Psychiatry and Neuroscience, Laval University, Quebec City, Quebec, Canada. Electronic address: denis.soulet@crchul.ulaval.ca.
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D056747:Immunomodulation / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D009197:Myenteric Plexus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism
chemical_list: C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; C532507:GPER1 protein, mouse; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: 17β-estradiol; GPER1; Ileum; Immunophenotype; Inflammation; Innate immune response; Intestine; MPTP; Myenteric plexus; Neuroprotection