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MicroRNA-1224-5p Aggravates Sepsis-Related Acute Lung Injury in Mice.

ABSTRACT: Oxidative stress and inflammation are implicated in the development of sepsis-related acute lung injury (ALI). MicroRNA-1224-5p (miR-1224-5p) plays critical roles in regulating inflammatory response and reactive oxygen species (ROS) production. The present study is aimed at investigating the role and underlying mechanisms of miR-1224-5p in sepsis-related ALI. Mice were intratracheally injected with lipopolysaccharide (LPS, 5 mg/kg) for 12 h to induce sepsis-related ALI. To manipulate miR-1224-5p level, mice were intravenously injected with the agomir, antagomir, or matched controls for 3 consecutive days. Murine peritoneal macrophages were stimulated with LPS (100 ng/mL) for 6 h to further validate the role of miR-1224-5p in vitro. To inhibit adenosine 5'-monophosphate-activated protein kinase alpha (AMPKα) or peroxisome proliferator activated receptor-gamma (PPAR-γ), compound C or GW9662 was used in vivo and in vitro. We found that miR-1224-5p levels in lungs were elevated by LPS injection, and that the miR-1224-5p antagomir significantly alleviated LPS-induced inflammation, oxidative stress, and ALI in mice. Conversely, the miR-1224-5p agomir aggravated inflammatory response, ROS generation, and pulmonary dysfunction in LPS-treated mice. In addition, the miR-1224-5p antagomir reduced, while the miR-1224-5p agomir aggravated LPS-induced inflammation and oxidative stress in murine peritoneal macrophages. Further findings revealed that miR-1224-5p is directly bound to the 3'-untranslated regions of PPAR-γ and subsequently suppressed PPAR-γ/AMPKα axis, thereby aggravating LPS-induced ALI in vivo and in vitro. We demonstrate for the first time that endogenous miR-1224-5p is a critical pathogenic factor for inflammation and oxidative damage during LPS-induced ALI through inactivating PPAR-γ/AMPKα axis. Targeting miR-1224-5p may help to develop novel approaches to treat sepsis-related ALI.

SUBMITTER: Liu B

PROVIDER: S-EPMC9256451 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSepsis can result in acute lung injury (ALI). Studies have shown that pharmacological inhibition of ferroptosis can treat ALI. However, the regulatory mechanisms of ferroptosis in sepsis-induced ALI remain unclear.MethodsTranscriptome sequencing was performed on lung tissue samples from 10 sepsis-induced mouse models of ALI and 10 control mice. After quality control measures, clean data were used to screen for differentially expressed genes (DEGs) between the groups. The DEGs were then overlapped with ferroptosis-related genes (FRGs) to obtain ferroptosis-related DEGs (FR-DEGs). Subsequently, least absolute shrinkage and selection operator (Lasso) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) were used to obtain key genes. In addition, Ingenuity Pathway Analysis (IPA) was employed to explore the disease, function, and canonical pathways related to the key genes. Gene set enrichment analysis (GSEA) was used to investigate the functions of the key genes, and regulatory miRNAs of key genes were predicted using the NetworkAnalyst and StarBase databases. Finally, the expression of key genes was validated with the GSE165226 and GSE168796 datasets sourced from the Gene Expression Omnibus (GEO) database and using quantitative real-time polymerase chain reaction (qRT-PCR).ResultsThirty-three FR-DEGs were identified between 1843 DEGs and 259 FRGs. Three key genes, Ncf2, Steap3, and Gclc, were identified based on diagnostic models established by the two machine learning methods. They are mainly involved in infection, immunity, and apoptosis, including lymphatic system cell migration and lymphocyte and T cell responses. Additionally, the GSEA suggested that Ncf2 and Steap3 were similarly enriched in mRNA processing, response to peptides, and leukocyte differentiation. Furthermore, a key gene-miRNA network including 2 key genes (Steap3 and Gclc) and 122 miRNAs, and a gene-miRNA network with 1 key gene (Steap3) and 3 miRNAs were constructed using NetworkAnalyst and StarBase, respectively. Both databases predicted that mmu-miR-15a-5p was the target miRNA of Steap3. Finally, Ncf2 expression was validated using both datasets and qRT-PCR, and Steap3 was validated using GSE165226 and qRT-PCR.ConclusionsThis study identified two FR-DEGs (Ncf2 and Steap3) associated with sepsis-induced ALI via transcriptome analyses, as well as their functional and metabolic pathways.

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MicroRNA-1224-5p Aggravates Sepsis-Related Acute Lung Injury in Mice.

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