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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial AIM2 alleviates antiviral-related neuro-inflammation in mouse models of Parkinson's disease
Wen-Juan Rui1,2, Sheng Li2,3, Lin Yang4
1Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
Inflammasome involvement in Parkinson's disease (PD) has been intensively investigated. Absent in melanoma 2 (AIM2) is an essential inflammasome protein known to contribute to the development of several neurological diseases. However, a specific role for AIM2 in PD has not been reported. In this study, we investigated the effect of AIM2 in the N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model by use of various knockout and bone marrow chimeric mice. The mechanism of action for AIM2 in PD was assessed by RNA-sequencing and in vitro primary microglial transfection. Results were validated in the A30P transgenic mouse model of PD. In the MPTP mouse model, AIM2 activation was found to negatively regulate neuro-inflammation independent of the inflammasome. Microglial AIM2 deficiency exacerbated behavioral and pathological features of both MPTP-induced and transgenic PD mouse models. Mechanistically, AIM2 reduced cyclic GMP-AMP synthase (cGAS)-mediated antiviral-related inflammation by inhibition of AKT-interferon regulatory factor 3 (IRF3) phosphorylation. These results demonstrate microglial AIM2 to inhibit the antiviral-related neuro-inflammation associated with PD and provide for a foundation upon which to identify new therapeutic targets for treatment of the disease.
Insights
Absent in melanoma 2 (AIM2) protein in microglia inhibits neuroinflammation, worsening Parkinson's disease (PD) symptoms when deficient. AIM2 targets cyclic GMP-AMP synthase (cGAS) to reduce antiviral-related inflammation, offering potential therapeutic avenues for PD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Inflammasome involvement in Parkinson's disease (PD) is extensively studied.
- Absent in melanoma 2 (AIM2) is a key inflammasome protein implicated in neurological disorders.
- The specific role of AIM2 in PD pathogenesis remains largely uncharacterized.
Purpose of the Study:
- To investigate the role and mechanism of AIM2 in the N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease.
- To elucidate the functional impact of microglial AIM2 on neuroinflammation and PD progression.
- To identify the molecular pathways through which AIM2 modulates PD-associated inflammation.
Main Methods:
- Utilized N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and A30P transgenic mouse models of PD.
- Employed knockout and bone marrow chimeric mice to assess AIM2 function.
- Conducted RNA-sequencing and in vitro primary microglial transfection to explore mechanisms.
Main Results:
- AIM2 activation negatively regulated neuroinflammation independently of the inflammasome in the MPTP model.
- Microglial AIM2 deficiency aggravated behavioral and pathological deficits in both MPTP-induced and transgenic PD models.
- AIM2 inhibited cyclic GMP-AMP synthase (cGAS)-mediated antiviral-related inflammation by suppressing AKT-interferon regulatory factor 3 (IRF3) phosphorylation.
Conclusions:
- Microglial AIM2 acts as a crucial inhibitor of antiviral-related neuroinflammation in Parkinson's disease.
- AIM2 deficiency exacerbates PD pathogenesis, highlighting its protective role.
- These findings establish AIM2 as a potential therapeutic target for mitigating neuroinflammation in PD.
