TIR-Domain-Containing Adapter-Inducing Interferon-β (TRIF) Is Essential for MPTP-Induced Dopaminergic Neuroprotection via Microglial Cell M1/M2 Modulation.

Minghui Shan,Liyi Ren,Jiali Peng,Huarong Hong,Sen Lin,Hongli Zhou,Xi Yang,Yuchen Du,Shurong Li,Jing Sun,Haixia Zhao,Bingyin Su,Yongmei Wu,Ming Yang

doi:10.3389/fncel.2017.00035

Abstract

Dynamic changes of two phenotypes of microglia, M1 and M2, are critically associated with the neurodegeneration of Parkinson's disease. However, the regulation of the M1/M2 paradigm is still unclear. In the MPTP induced neurodegeneration model, we examined the concentration of dopamine (DA) related metabolites and the survival of tyrosine hydroxylase (TH) positive cells in WT and Trif −/− mice. In in vitro experiments, MN9D cells were co-cultured with BV2 cells to mimic the animal experiments. Inhibition of TRIF aggravated TH+ cell loss, and DA-related metabolites decreased. TRIF inhibition was able to interrupt the microglial M1/M2 dynamic transformation. More BV2 cells were activated and migrated across the membrane of transwell plates by siTRIF treatment. Also, TRIF interruption inhibits the transformation of BV2 cells from the M1 to M2 phenotype which played a beneficial role in neuronal degenerative processes, and increased MN9D apoptosis. Moreover, MPP+ treatment decreases the (DAT) dopamine transporter and TH synthesis by MN9D. Taken together, the current results suggest that TRIF plays a key switch function in contributing to the microglial M1/M2 phenotype dynamic transformation. The interruption of TRIF may decrease the survival of MN9D cells as well as DAT and TH protein production. The current study sheds some light on the PD mechanism research by innate inflammation regulation.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system that affects some people above the age of 60 worldwide
We investigate the role of TRIF in regulating the transformation of the microglial M1/M2 phenotype in the mesencephalon-derived dopaminergic neuronal cell line (MN9D) and demonstrate that microglial TRIF plays an important role in regulating MN9D cell survival and microglial M1/M2 modulation
The present results suggest that the typical microglial M1/M2 markers can be changed by MPP+-treated MN9D cells and the paradigm regulation depends on injured MN9D cell stimulation

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system that affects some people above the age of 60 worldwide. Neuroinflammation is a prominent event that affects the clinical course of Parkinson’s disease (Gao and Hong, 2008; Glass et al, 2010). Molecular and clinical evidence has shown significant increase of microglial activation, accumulation, and concentration of inflammatory factors in pathological neurodegenerative diseases (LaVoie et al, 2004; Ouchi et al, 2005; Gerhard et al, 2006; Glass et al, 2010). In PD patients the presence of persistent microglia activated and accumulated in the vicinity of the neurons in substantia nigra (Ferrari and Tarelli, 2011; Barcia et al, 2013) has been shown. The mechanism how microglia maintains the activation phenotype is still unclear based on current evidence, it has been suggested that microglia activation may contribute to the degeneration of dopaminergic neurons (Barcia et al, 2013)

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