Dataset Information

Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4.

ABSTRACT: Acute respiratory distress syndrome (ARDS) is an outcome of an accelerated immune response that starts initially as a defensive measure, however, due to non-canonical signaling, it later proves to be fatal not only to the affected tissue but to the whole organ system. microRNAs are known for playing a decisive role in regulating the expression of genes involved in diverse functions such as lung development, repair, and inflammation. In-silico analyses of clinical data and microRNA databases predicted a probable interaction between miRNA-34a (miR-34a), mitogen-activated protein kinase 1 (ERK), and kruppel like factor 4 (Klf4). Parallel to in silico results, here, we show that intra-tracheal instillation of lipopolysaccharides (LPS) to mice enhanced miR-34a expression in lung macrophages. Inhibition of miR-34a significantly improved lung histology, whereas over-expression of miR-34a worsened the lung injury phenotype. miR-34a over-expression in macrophages were also demonstrated to favour pro-inflammatory M1 phenotype and inhibition of M2 polarization. In a quest to confirm this likely interaction, expression profiles of Klf4 as the putative target were analyzed in different macrophage polarizing conditions. Klf4 expression was found to be prominent in the miR-34a inhibitor-treated group but down-regulated in the miR-34a mimic treated group. Immuno-histopathological analyses of lung tissue from the mice treated with miR-34a inhibitor also showed reduced inflammatory M1 markers as well as enhanced cell proliferation. The present study indicates that miR-34a intensified LPS-induced lung injury and inflammation by regulating Klf4 and macrophage polarization, which may serve as a potential therapeutic target for acute lung injury/ARDS.

SUBMITTER: Khan MJ

PROVIDER: S-EPMC7563942 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4.

Khan Mohd Junaid MJ Singh Prithvi P Dohare Ravins R Jha Rishabh R Rahmani Arshad H AH Almatroodi Saleh A SA Ali Shakir S Syed Mansoor Ali MA

Genes 20200820 9

Acute respiratory distress syndrome (ARDS) is an outcome of an accelerated immune response that starts initially as a defensive measure, however, due to non-canonical signaling, it later proves to be fatal not only to the affected tissue but to the whole organ system. microRNAs are known for playing a decisive role in regulating the expression of genes involved in diverse functions such as lung development, repair, and inflammation. In-silico analyses of clinical data and microRNA databases pred ...[more]

PMID: 32825525

Similar Datasets

Project description:Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into "classically activated macrophages" (M1) and "alternatively activated macrophages" (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-α (TNF-α), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI+Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline+Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway.

Project description:Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 μg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1β) and reduced anti-inflammatory cytokines (TGF-β and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.

Dataset Information

Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4.

Publications

Inhibition of miRNA-34a Promotes M2 Macrophage Polarization and Improves LPS-Induced Lung Injury by Targeting Klf4.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets