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miR-214-3p Deficiency Enhances Caspase-1-Dependent Pyroptosis of Microglia in White Matter Injury
Liufang He1, Tingyan Wei1, Yong Huang1
1Department of Neonatology, Affiliated Longhua People's Hospital, Southern Medical University (Longhua People's Hospital), Shenzhen, Guangdong 518190, China.
Abstract:
White matter injury (WMI) is the most frequent impairment of neurodevelopment in preterm infants. Here, we report that the caspase-1 inflammasome is abundantly activated in the microglia of WMI mice and results in increased pyroptosis of microglia. Pharmacology inhibition of caspase-1 cleavage alleviated the pathogenesis of WMI mice. The expression of microRNA miR-214-3p was largely reduced in the microglia of WMI mice compared to controls. Compromised expression of miR-214-3p on microglia gives rise to the inflammasome activation and microglial pyroptosis. Treatment with miR-214-3p agomir is sufficient to relieve the white matter lesion and demyelination in WMI mice. miR-214-3p is able to bind to the 3' region of the NLRP-3 inflammasome compartment NEK7, preventing the transcription of NEK7 mRNA. As a result, in WMI mice, the lack of miR-214-3p leads to the accumulation of NEK7 which supports NLRP 3 inflammasome activation, microglial pyroptosis, and white matter pathogenesis.
Insights
The caspase-1 inflammasome drives microglial pyroptosis in white matter injury (WMI). Restoring microRNA miR-214-3p levels protects against WMI pathogenesis by inhibiting inflammasome activation.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- White matter injury (WMI) is a primary cause of neurodevelopmental impairment in preterm infants.
- Microglial activation and pyroptosis are key pathological features of WMI.
Purpose of the Study:
- To investigate the role of the caspase-1 inflammasome and microRNA miR-214-3p in the pathogenesis of WMI.
- To explore therapeutic strategies targeting these pathways for WMI treatment.
Main Methods:
- Utilized a mouse model of WMI.
- Assessed caspase-1 inflammasome activation and microglial pyroptosis.
- Quantified microRNA miR-214-3p expression levels.
- Administered pharmacological inhibitors and miR-214-3p agomir for therapeutic intervention.
- Investigated the molecular interaction between miR-214-3p and NEK7 mRNA.
Main Results:
- Caspase-1 inflammasome activation and microglial pyroptosis were significantly increased in WMI mice.
- Pharmacological inhibition of caspase-1 cleavage ameliorated WMI pathology.
- miR-214-3p expression was downregulated in microglia from WMI mice.
- Restoring miR-214-3p levels via agomir treatment reduced white matter lesions and demyelination.
- miR-214-3p directly targets NEK7 mRNA, a component of the NLRP-3 inflammasome, thereby suppressing its transcription.
Conclusions:
- The caspase-1 inflammasome and subsequent microglial pyroptosis are critical drivers of WMI pathogenesis.
- Reduced miR-214-3p expression contributes to WMI by promoting inflammasome activation via NEK7.
- miR-214-3p represents a potential therapeutic target for mitigating WMI and its neurodevelopmental consequences.
