GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease.

TitleGPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease.
Publication TypeJournal Article
Year of Publication2015
AuteursCôté, M, Bourque, M, Poirier, A-A, Aubé, B, Morissette, M, Di Paolo, T, Soulet, D
JournalNeurobiol Dis
Volume82
Pagination99-113
Date Published2015 Oct
ISSN1095-953X
KeywordsAnimals, Benzodioxoles, Dopaminergic Neurons, Estradiol, Immunomodulation, Mice, Myenteric Plexus, Neuroprotection, Neuroprotective Agents, NF-kappa B, Nitric Oxide Synthase Type II, Parkinsonian Disorders, Quinolines, Receptors, Estrogen, Receptors, G-Protein-Coupled
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.

DOI10.1016/j.nbd.2015.05.017
Alternate JournalNeurobiol. Dis.
PubMed ID26051538
Grant List275325 / / Canadian Institutes of Health Research / Canada