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Microglia Regulate Blood-Brain Barrier Integrity via MiR-126a-5p/MMP9 Axis during Inflammatory Demyelination
Zhongwang Yu1, Xue Fang1,2, Weili Liu1
1Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, SMMU, Shanghai, 200433, China.
Abstract:
Blood-brain barrier (BBB) impairment is an early prevalent feature of multiple sclerosis (MS), and remains vital for MS progression. Microglial activation precedes BBB disruption and cellular infiltrates in the brain of MS patients. However, little is known about the function of microglia in BBB impairment. Here, microglia acts as an important modulator of BBB integrity in inflammatory demyelination. Microglial depletion profoundly ameliorates BBB impairment in experimental autoimmune encephalomyelitis (EAE). Specifically, miR-126a-5p in microglia is positively correlated with BBB integrity in four types of MS plaques. Mechanistically, microglial deletion of miR-126a-5p exacerbates BBB leakage and EAE severity. The protective effect of miR-126a-5p is mimicked and restored by specific inhibition of MMP9 in microglia. Importantly, Auranofin, an FDA-approved drug, is identified to protect BBB integrity and mitigate EAE progression via a microglial miR-126a-5p dependent mechanism. Taken together, microglia can be manipulated to protect BBB integrity and ameliorate inflammatory demyelination. Targeting microglia to regulate BBB permeability merits consideration in therapeutic interventions in MS.
Insights
Microglia modulate blood-brain barrier integrity in multiple sclerosis (MS). Targeting microglial miR-126a-5p protects the BBB and reduces disease severity in experimental autoimmune encephalomyelitis (EAE).
Area of Science:
- Neuroimmunology
- Molecular Biology
Background:
- Blood-brain barrier (BBB) impairment is a key feature of multiple sclerosis (MS) progression.
- Microglial activation is observed early in MS, but their role in BBB disruption is unclear.
Purpose of the Study:
- To investigate the role of microglia in modulating BBB integrity during inflammatory demyelination.
- To identify molecular mechanisms by which microglia influence BBB function in MS.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) model in mice.
- Microglial depletion studies.
- Analysis of microRNA-126a-5p (miR-126a-5p) expression in microglia.
- Assessment of BBB permeability and EAE severity.
- Inhibition of matrix metalloproteinase-9 (MMP9).
- Treatment with Auranofin.
Main Results:
- Microglial depletion significantly reduced BBB impairment in EAE.
- Microglial miR-126a-5p levels correlated positively with BBB integrity in MS plaques.
- Deletion of miR-126a-5p in microglia worsened BBB leakage and EAE.
- Inhibition of MMP9 in microglia mimicked the protective effects of miR-126a-5p.
- Auranofin protected BBB integrity and mitigated EAE via a microglial miR-126a-5p dependent pathway.
Conclusions:
- Microglia are critical modulators of BBB integrity in inflammatory demyelination.
- Microglial miR-126a-5p plays a protective role by regulating MMP9.
- Targeting microglia to control BBB permeability offers a potential therapeutic strategy for MS.
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