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MicroRNA-138-5p Regulates Hippocampal Neuroinflammation and Cognitive Impairment by NLRP3/Caspase-1 Signaling Pathway
Xiaojin Feng1,2, Jialing Hu1, Fenfang Zhan1
1Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.
Purpose:
Neuroinflammation is an essential causative factor in the pathogenesis and progression of cognitive impairment. The present study aims to evaluate the critical role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment through the NLRP3/caspase-1 signaling pathway in rats.
Material And Methods:
We established the cognitive impairment rat model and RM (Rat microglia) microglial cellular inflammation model by intracerebroventricular (icv) injection or stimulation of lipopolysaccharide (LPS). Morris water maze (MWM) and Y-maze tests were performed to assess the cognitive behaviors. Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme-linked immune-sorbent assay (ELISA) and Western blot analysis were utilized to evaluate mRNA or protein expression. Bioinformatic analysis and dual-luciferase reporter gene assay were performed to verify the targeting relationship between NLRP3 and miR-138-5p. Besides, Hematoxylin and eosin (H&E) staining and immunohistochemistry were applied to observe the neuronal morphology and detect the positive cells of the hippocampus, respectively.
Results:
Compared to the control groups, LPS-treated rats exhibited significantly impaired learning and memory in MWM and Y-maze tests. The expression of NLRP3, caspase-1 and pro-inflammation cytokines (IL-1β and IL-18) were upregulated, while miR-138-5p was downregulated both in rat hippocampus and RM cells treated with LPS. MiR-138-5p is downregulated in microarray data of cognitive impairment animals and could directly target the 3'-UTR of NLRP3. Furthermore, upregulation of miR-138-5p improved impaired cognitive functions, while inhibited hippocampal neuroinflammation demonstrated by decreased expression of NLRP3/caspase-1 axis, pro-inflammation cytokines and microglial activation. This study demonstrates for the first time that miR-138-5p suppresses the hippocampal NLRP3/caspase-1 signaling pathway activation in cognition impaired rats.
Conclusion:
The low expression of miR-138-5p after LPS administration may contribute to the activation of the NLRP3/caspase-1 pathway, leading to hippocampal neuroinflammation and cognitive impairment in rat models. These findings indicate a promising therapeutic avenue for cognitive disorders.
Insights
Low microRNA-138-5p expression exacerbates neuroinflammation and cognitive impairment by activating the NLRP3/caspase-1 pathway. Restoring miR-138-5p levels offers a potential therapeutic strategy for cognitive disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Neuroinflammation is a key driver in cognitive impairment pathogenesis.
- MicroRNAs play crucial roles in regulating cellular processes, including inflammation.
Purpose of the Study:
- To investigate the role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment.
- To elucidate the involvement of the NLRP3/caspase-1 signaling pathway in this process.
Main Methods:
- Established rat models of cognitive impairment and microglial inflammation using lipopolysaccharide (LPS).
- Assessed cognitive function via Morris water maze and Y-maze tests.
- Quantified gene and protein expression using qRT-PCR, ELISA, and Western blot.
- Verified the targeting relationship between NLRP3 and miR-138-5p using bioinformatic analysis and dual-luciferase reporter assays.
Main Results:
- LPS administration induced cognitive deficits, upregulated NLRP3, caspase-1, IL-1β, and IL-18, and downregulated miR-138-5p in rat hippocampus and microglia.
- miR-138-5p directly targets the 3'-UTR of NLRP3.
- Upregulating miR-138-5p ameliorated cognitive impairment and reduced neuroinflammation by suppressing the NLRP3/caspase-1 pathway and microglial activation.
Conclusions:
- Reduced miR-138-5p expression contributes to NLRP3/caspase-1 pathway activation, driving hippocampal neuroinflammation and cognitive impairment.
- miR-138-5p acts as a suppressor of the NLRP3/caspase-1 signaling pathway in cognitive impairment.
- Targeting miR-138-5p presents a potential therapeutic strategy for cognitive disorders.
