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Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
TIR-Domain-Containing Adapter-Inducing Interferon-β (TRIF) Is Essential for MPTP-Induced Dopaminergic Neuroprotection
Minghui Shan1, Sen Lin2, Shurong Li3
1Development and Regeneration Key Lab of Sichuan Province, Department of Pathology, Department of Anatomy and Histology and Embryology, Chengdu Medical CollegeChengdu, China; Department of Clinical Pathology, Nanyang Central HospitalNangyang, China.
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.
Insights
Toll-like receptor adaptor TRIF regulates microglial M1/M2 phenotype shifts in Parkinson's disease models. TRIF inhibition worsens neurodegeneration and dopamine neuron loss, highlighting its protective role.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial M1 and M2 phenotypes dynamically change during Parkinson's disease (PD) neurodegeneration.
- The regulatory mechanisms governing the microglial M1/M2 paradigm in PD remain incompletely understood.
Purpose of the Study:
- To investigate the role of TRIF (Toll-interleukin 1 receptor domain-containing adapter inducing interferon-β) in regulating microglial M1/M2 phenotype dynamics.
- To examine the impact of TRIF inhibition on dopaminergic neuron survival and dopamine metabolism in PD models.
Main Methods:
- Utilized MPTP-induced neurodegeneration mouse model and in vitro co-culture systems (MN9D and BV2 cells).
- Assessed dopamine metabolites, tyrosine hydroxylase (TH)-positive cell survival, and microglial activation/migration.
- Employed small interfering RNA (siRNA) targeting TRIF (siTRIF) and MPP+ treatment.
Main Results:
- TRIF inhibition exacerbated TH-positive cell loss and decreased dopamine metabolites in MPTP models.
- TRIF inhibition disrupted microglial M1/M2 dynamic transformation, promoting M1 phenotype and inhibiting beneficial M2 transformation.
- siTRIF treatment increased BV2 cell activation and migration, and led to increased MN9D cell apoptosis.
- MPP+ treatment reduced dopamine transporter (DAT) and TH synthesis in MN9D cells.
Conclusions:
- TRIF acts as a crucial regulator of microglial M1/M2 phenotype dynamics.
- TRIF interruption negatively impacts dopaminergic neuron survival and dopamine-related protein production.
- This study provides insights into PD pathogenesis via innate inflammation regulation by TRIF.
