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Published on: January 7, 2014
Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice
Hernan Cardenas1, Laurel M Bolin
1The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA.
Abstract:
Reactive gliosis, the cellular manifestation of neuroinflammation, is a pathological hallmark of neurodegenerative diseases including Parkinson's disease. The persistent gliosis observed in the Parkinson's disease substantia nigra (SN) and in humans and animals exposed to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) may represent a chronic inflammatory response that contributes to pathology. We have previously shown that in the absence of interleukin-6 (IL-6) dopaminergic neurons are more vulnerable to MPTP. Since IL-6 is both an autocrine and paracrine proliferation factor for CNS glia, we investigated reactive gliosis in MPTP-lesioned IL-6 (-/-) mice. While astrogliosis was similar in injured IL-6 (+/+) and IL-6 (-/-) SN pars compacta (pc), microgliosis was severely compromised in IL-6 (-/-) mice. In the absence of IL-6, an acute reactive microgliosis was transient with a complete absence of reactive microglia at day 7 post-lesion. Extensive reactive microgliosis was observed in the SNpc of MPTP-lesioned IL-6 (+/+) mice. Because glial derived inducible nitric oxide synthase (iNOS) has been implicated in dopaminergic cell death, we examined glial iNOS expression in the IL-6 genotypes to determine if it correlated with the greater vulnerability and reduced microgliosis observed in the MPTP-lesioned IL-6 (-/-) nigrostriatal system. Both reactive microglia and astrocytes expressed iNOS in the lesioned SNpc. In the IL-6 (-/-) mice, microglial iNOS expression diminished as reactive microgliosis declined. The data suggest IL-6 regulation of microglia activation, while iNOS expression appears to be secondary to cell activation.
Insights
Interleukin-6 (IL-6) is crucial for sustained microglial activation in response to neuroinflammation, as seen in Parkinson's disease models. Its absence leads to transient microgliosis and increased neuronal vulnerability.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Reactive gliosis, a hallmark of neuroinflammation, is implicated in neurodegenerative diseases like Parkinson's disease.
- Interleukin-6 (IL-6) plays a role in glial cell proliferation and has been shown to protect dopaminergic neurons from MPTP neurotoxicity.
- The role of IL-6 in regulating microgliosis and astrogliosis in response to neurotoxic injury remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of IL-6 in reactive gliosis following MPTP-induced neurotoxicity.
- To determine the impact of IL-6 deficiency on microglial and astrocyte activation in the substantia nigra pars compacta (SNpc).
- To examine the expression of inducible nitric oxide synthase (iNOS) in glial cells in the context of IL-6 deficiency and neuroinflammation.
Main Methods:
- MPTP neurotoxicity model in wild-type (IL-6 +/+) and IL-6 knockout (IL-6 -/-) mice.
- Immunohistochemical analysis of glial markers (microglia and astrocytes) in the SNpc.
- Assessment of inducible nitric oxide synthase (iNOS) expression in glial cells.
Main Results:
- Astrogliosis was comparable between IL-6 (+/+) and IL-6 (-/-) mice post-MPTP lesion.
- Microgliosis was severely impaired in IL-6 (-/-) mice, with reactive microglia being transient and absent by day 7.
- Inducible nitric oxide synthase (iNOS) was expressed by both microglia and astrocytes, with microglial iNOS expression declining alongside microgliosis in IL-6 (-/-) mice.
Conclusions:
- IL-6 is essential for sustained microglial activation and the development of reactive microgliosis in the MPTP neurotoxicity model.
- The findings suggest that IL-6 regulates microglial activation, while iNOS expression is secondary to the activation state of these cells.
- IL-6 deficiency exacerbates dopaminergic neuron vulnerability, potentially due to impaired microglial response and subsequent inflammatory processes.
