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Published on: January 30, 2014
MicroRNA210 Suppresses Mitochondrial Metabolism and Promotes Microglial Activation in Neonatal Hypoxic-Ischemic Brain
Shirley Hu1, Yanelly Lopez-Robles1, Guofang Shen1,2
1The Lawrence D. Longo Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
Abstract:
Neuroinflammation is the major contributor to the pathology of neonatal hypoxic-ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms remain elusive. In the present study, using miR210 knockout (KO) mice and microglial cultures, we tested the hypothesis that miR210 promotes microglial activation and neuroinflammation through suppressing mitochondrial function in microglia after HI. Neonatal HI brain injury was conducted on postnatal day 9 (P9) wild-type (WT) and miR210 knockout (KO) mouse pups. We found that miR210 KO significantly reduced brain infarct size at 48 h and improved long-term locomotor functions assessed by an open field test three weeks after HI. Moreover, miR210 KO mice exhibited reduced IL1β levels, microglia activation and immune cell infiltration after HI. In addition, in vitro studies of microglia exposed to oxygen-glucose deprivation (OGD) revealed that miR210 inhibition with LNA reduced OGD-induced expression of Il1b and rescued OGD-mediated downregulation of mitochondrial iron-sulfur cluster assembly enzyme (ISCU) and mitochondrial oxidative phosphorylation activity. To validate the link between miR210 and microglia activation, isolated primary murine microglia were transfected with miR210 mimic or negative control. The results showed that miR210 mimic downregulated the expression of mitochondrial ISCU protein abundance and induced the expression of proinflammatory cytokines similar to the effect observed with ISCU silencing RNA. In summary, our results suggest that miR210 is a key regulator of microglial proinflammatory activation through reprogramming mitochondrial function in neonatal HI brain injury.
Insights
MicroRNA210 (miR210) inhibition protects against neonatal brain injury by reducing neuroinflammation. This study reveals miR210 promotes microglial activation and brain damage by impairing mitochondrial function.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Neonatal hypoxic-ischemic (HI) brain injury involves significant neuroinflammation.
- MicroRNA210 (miR210) inhibition shows neuroprotective effects after HI.
- The precise mechanisms by which miR210 influences HI pathology are not fully understood.
Purpose of the Study:
- To investigate the role of miR210 in microglial activation and neuroinflammation following neonatal HI.
- To test the hypothesis that miR210 exacerbates HI brain injury by suppressing microglial mitochondrial function.
Main Methods:
- Utilized miR210 knockout (KO) mice and primary microglial cultures.
- Induced neonatal HI brain injury in wild-type and miR210 KO mouse pups.
- Performed in vitro oxygen-glucose deprivation (OGD) on microglial cells.
- Assessed brain infarct size, locomotor function, inflammatory markers (IL1β), microglial activation, and mitochondrial function (ISCU, oxidative phosphorylation).
Main Results:
- miR210 KO significantly reduced brain infarct size and improved long-term locomotor function post-HI.
- miR210 KO mice showed decreased IL1β levels, reduced microglial activation, and less immune cell infiltration.
- In vitro, miR210 inhibition lessened OGD-induced IL1β expression and restored mitochondrial function.
- Overexpression of miR210 in microglia mimicked the effects of ISCU silencing, increasing proinflammatory cytokines.
Conclusions:
- miR210 acts as a key regulator of microglial proinflammatory activation in neonatal HI brain injury.
- miR210 promotes neuroinflammation and brain damage by negatively impacting microglial mitochondrial function.
- Targeting miR210 may offer a therapeutic strategy for neonatal HI brain injury.
