Blocking the LncRNA MALAT1/miR-224-5p/NLRP3 Axis Inhibits the Hippocampal Inflammatory Response in T2DM With OSA

Abstract

Studies have shown that diabetes can cause cognitive dysfunction, and cognitive dysfunction in patients with diabetes combined with obstructive sleep apnea (OSA) is more severe. LncRNAs are known to be associated with type 2 diabetes mellitus (T2DM) with OSA. This study aimed to investigate the role and underlying mechanism of the lncRNA MALAT1/miR-224-5p/NLRP3 axis in T2DM with OSA. qRT-PCR was used to quantify the expression of MALAT1, miR-224-5p, and NLRP3 in brain tissues. NLRP3 expression was assessed by immunohistochemistry (IHC) and immunofluorescent labeling. The interaction involving MALAT1, miR-224-5p, and NLRP3 was evaluated by transfection. Western blotting was utilized to evaluate the expression levels of the pathway-related proteins NLRP3, caspase 1, tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) both in vitro and in vivo. qRT-PCR was used to assess the mRNA expression levels of NLRP3, caspase 1, TNF-α and IL-1β both in vitro and in vivo. In brain tissues of T2DM with OSA, MALAT1 and NLRP3 were overexpressed, while miR-224-5p was downregulated, which was consistent with subsequent cell experiments. We screened the miRNAs that could bind to MALAT1 and NLRP3 by the StarBase database and the TargetScanMouse7.2 website. Our research showed that among these miRNAs, the level of miR-224-5p was most significantly negatively correlated with the levels of MALAT1 and NLRP3. Also, a firefly luciferase assay showed that miR-224-5p, which is a target of MALAT1, directly reduced the expression of the downstream protein NLRP3. Overexpression of miR-224-5p significantly inhibited the expression levels of NLRP3, caspase 1, TNF-α and IL-1β in vitro. MALAT1 promoted NLRP3 expression by acting as a competing endogenous RNA and sponging miR-224-5p. MiR-224-5p reduces microglial inflammation activation through the regulation of NLRP3 expression, which ultimately affected the NLRP3/IL-1β pathway in the hippocampus. This suggests that miR-224-5p may serve as a potential target for T2DM and OSA therapy.

HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2

“… 50 , 51 Overexpression of miR-224-5p can significantly inhibit the expression of TNF-α and IL-1β in the hippocampus following onset of type 2 diabetes mellitus in association with obstructive sleep apnea. 52 Moreover, miR-224 suppresses airway epithelial cell inflammation in PM2.5-induced asthmatic mice due to its ability in reducing the expression of pro-inflammatory mediators transforming growth factor-β (TGF-β), MMP9, TIMP-1, and RORγt. 53 These reports highlighted the protection from inflammation conferred by miR-224.…”

LncRNA CD27-AS1 promotes acute myeloid leukemia progression through the miR-224-5p/PBX3 signaling circuit

“…Herein, we demonstrated that CD27-AS1 promoted AML progression through targeting miR-224-5p. Aside from CD27-AS1, miR-224-5p was indeed regulated by multiple lncRNAs, such as LncRNA MALAT1 34 and NEAT1 35 in other human diseases. MALAT1 promoted the malignant phenotype of AML cells 36 , whereas lncRNA NEAT1 inhibited the development of AML 37 .…”

Up－Regulated miR-224-5p Can Target the Expression of Neuritin in Hearing Loss

“…Zhu[36] found that LINC00094 inhibited endotoxin-1 expression by up-regulating miR-224-4p/miR-497-5p, promoted the expression of ZO-1, Okrudin and Claudine-5, and nally alleviated BBB Permeability in the AD microenvironment. Du [37] found that MiR-224-5p can reduce the activation of microglial in ammation by regulating the expression of NLRP3. Liu[38] found that miR-224-5p plays a vital role in hypoxic neuronal injury through NR4A1, which may be an important regulatory mechanism of neuronal OGD injury.…”