MicroRNA‑17 contributes to the suppression of the inflammatory response in lipopolysaccharide‑induced acute lung injury in mice via targeting the toll‑like receptor 4/nuclear factor‑κB pathway.

Abstract

Acute lung injury (ALI) is a common lung disease with a high mortality rate, which is characterized by an excessive uncontrolled inflammatory response. MicroRNA (miR)-17 has previously emerged as a novel regulatory molecule of inflammatory response in various complex diseases; however, the anti-inflammatory action and associated molecular mechanisms of miR-17 in ALI have not been fully elucidated. The aim of the present study was to investigate the role of miR-17 in the inflammatory response in ALI and to elucidate the potential underlying mechanism. Using a lipopolysaccharide (LPS)-induced ALI mouse model, it was observed that miR-17 was significantly downregulated in lung tissues compared with the control group. In this model, ectopic expression of miR-17 attenuated lung pathological damage, reduced lung wet/dry ratio and lung permeability, and increased survival rate in ALI mice. In addition, agomiR-17 injection significantly suppressed LPS-induced inflammation, as evidenced by a reduction in the activity of myeloperoxidase and the production of interleukin (IL)-6, IL-1β and tumor necrosis factor-α in lung tissues. Of note, toll-like receptor (TLR) 4, an upstream regulator of the nuclear factor (NF)-κB inflammatory signaling pathway, was directly targeted by miR-17, and its translation was suppressed by miR-17 in vitro and in vivo. Using an LPS-induced RAW264.1 macrophage injury model, it was observed that miR-17 overexpression suppressed the pro-inflammatory effect of LPS, while these inhibitory effects were markedly abrogated by TLR4 overexpression. In addition, TLR4 knockdown by si-TLR4 mimicked the effects of miR-17 overexpression on LPS-induced cytokine secretion in the in vitro model. Further experiments revealed that miR-17 significantly reduced the expression of key proteins in the NF-κB pathway, including IKKβ, p-IκBα and nuclear p-p65, and suppressed the NF-κB activity in ALI mice. Collectively, these results indicated that miR-17 protected mice against LPS-induced lung injury via inhibiting inflammation by targeting the TLR4/NF-κB pathway; therefore, miR-17 may serve as a potential therapeutic target for ALI.