LncRNA 4344 promotes NLRP3-related neuroinflammation and cognitive impairment by targeting miR-138-5p

Abstract

Objective: Cognitive impairment is a common neurological disease of which NLRP3-related neuroinflammation has been demonstrated to be an essential mediator. Previous studies have indicated that long non-coding RNAs (lncRNAs) are critical for the development of neurological disorders. However, the roles and functions of lncRNA 4344 in neuroinflammation during cognitive impairment are unknown and need to be further elucidated.

Methods: Lipopolysaccharide (LPS)-induced rat cognitive impairment and rat microglia (RM) cell inflammation models were established in vitro and in vivo. The Morris water maze test was used to evaluate the cognitive behavior of the rats. Gene expression was assessed using real-time quantitative polymerase chain reaction, and protein levels using enzyme-linked immunosorbent assay, or western blot analysis. The targeting relationship between lncRNA 4344, miR-138-5p, and NLRP3 was identified using bioinformatics analysis and a dual-luciferase reporter gene assay. Hematoxylin-Eosin and Nissl stainings, terminal deoxynucleotidyl transferase dUTP nick end labeling, or immunofluorescence staining assays were performed to detect pathological changes, neuronal apoptosis, or positive cells in hippocampal tissues, respectively.

Results: The expression levels of lncRNA 4344 and NLRP3 were upregulated in the hippocampal tissues of LPS-treated rats and RM cells, and showed a strong positive correlation between each other. LncRNA 4344 overexpression further enhanced the expression of NLRP3 and its downstream genes (caspase-1, IL-1β, and IL-18), as well as neuronal apoptosis in LPS-stimulated RM cells, whereas lncRNA 4344 silencing attenuated the inflammatory injuries. Moreover, miR-138-5p was the direct target of lncRNA 4344 and was downregulated in the RM cell inflammation model. We also found that miR-138-5p directly reduced the expression of NLRP3 and its downstream genes. Subsequently, the results of the animal experiments showed that the lncRNA 4344/miR-138-5p/NLRP3 axis plays an essential role in regulating the cognitive behavior, pathological changes and apoptosis of hippocampal neurons, expression of inflammation-related factors (NLRP3, caspase-1, IL-1β, and IL-18), and microglial activation in LPS-induced cognitive impairment rats.

Conclusion: Our results demonstrated for the first time that lncRNA 4344 regulates NLRP3-related neuroinflammation and cognitive impairment by targeting miR-138-5p, providing a possible target for the treatment of diseases characterized by a cognitive deficit.

Keywords: Cognitive impairment; LncRNA 4344; NLRP3; Neuroinflammation; miR-138-5p.