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.
Highlights
Acute respiratory distress syndrome (ARDS) is inflammatory disorder that is characterized by respiratory failures resulting in considerable mortality rates worldwide [1]
We show the role of kruppel like factor 4 (Klf4), one of the downstream targets of miR-34a, in macrophage polarization and inflammation
The GEO2R web tools were accessed for doing the R-based analysis of Gene Expression Omnibus (GEO) datasets to identify the differentially expressed genes (DEGs) between two groups, i.e., sepsis only and sepsis with acute lung injury
Summary
Acute respiratory distress syndrome (ARDS) is inflammatory disorder that is characterized by respiratory failures resulting in considerable mortality rates worldwide [1]. Macrophages play a significant part in innate immune responses, progression and resolution of ARDS, and related inflammatory conditions [6,7,8]. Variable expressions of miRNAs under a different set of conditions influence the macrophages to polarize to pro-inflammatory or anti-inflammatory states, either aggravating the state of inflammation or alleviating it [10]. Kruppel like factor 4 (Klf4) is one of the prominent ones that modulates macrophages to polarize to anti-inflammatory M2 phenotype known for resolution of inflammation and tissue repair [21]. Klf is known to regulate the expression of a gene involved in diverse cellular processes that are context-dependent, such as cell growth arrest, cell survival, cell differentiation, and resolution of inflammation [22,23,24,25,26]
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