Down-regulation of miR-let-7e attenuates LPS-induced acute lung injury in mice via inhibiting pulmonary inflammation by targeting SCOS1/NF-κB pathway.

Jun Liu,Wuquan Li,Wenjun Liu,Gang Ji,He Jiang,Yalong Han,Wentao Zhang

doi:10.1042/bsr20201089

Jun Liu, Wuquan Li + Show 5 more

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https://doi.org/10.1042/bsr20201089

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Abstract

Excessive pulmonary inflammatory response is critical in the development of acute lung injury (ALI). Previously, microRNAs (miRNAs) have been recognized as an important regulator of inflammation in various diseases. However, the effects and mechanisms of miRNAs on inflammatory response in ALI remain unclear. Herein, we tried to screen miRNAs in the processes of ALI and elucidate the potential mechanism. Using a microarray assay, microRNA let-7e (let-7e) was chose as our target for its reported suppressive roles in several inflammatory diseases. Down-regulation of let-7e by antagomiR-let-7e injection attenuated LPS-induced acute lung injury. We also found that antagomiR-let-7e could obviously improve the survival rate in ALI mice. Moreover, antagomiR-let-7e treatment reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) in bronchoalveolar lavage fluid (BALF) of LPS-induced ALI mice. Luciferase reporter assays confirmed that suppressor of cytokine signaling 1 (SOCS1), a powerful attenuator of nuclear factor kappa B (NF-κB) signaling pathway, was directly targeted and suppressed by let-7e in RAW264.7 cells. In addition, it was further observed that SOCS1 was down-regulated, and inversely correlated with let-7e expression levels in lung tissues of ALI mice. Finally, down-regulation of let-7e suppressed the activation of NF-κB pathway, as evidenced by the reduction of p-IκBα, and nuclear p-p65 expressions in ALI mice. Collectively, our findings indicate that let-7e antagomir protects mice against LPS-induced lung injury via repressing the pulmonary inflammation though regulation of SOCS1/NF-κB pathway, and let-7e may act as a potential therapeutic target for ALI.

Highlights

Acute lung injury (ALI) is a serious inflammatory lung disease with the high mortality (35–40%), which usually caused by various direct or indirect factors, including the trauma, blood transfusion, and infection [1]
After dye injection 2 h, mice were killed and the dye was extracted by incubation in formamide for 24 h at 60◦C
We found let-7e was highly expressed in lung tissues and bronchoalveolar lavage fluid (BALF) in ALI mice

Summary

Introduction

Acute lung injury (ALI) is a serious inflammatory lung disease with the high mortality (35–40%), which usually caused by various direct or indirect factors, including the trauma, blood transfusion, and infection [1]. In spite of considerable effort, there are still no effective therapeutic regimens for this disease [2]. Excessive inflammatory reaction in the lung tissues is the main pathological feature of ALI [3]. Once toll-like receptors (TLRs) are activated, it can subsequently activate nuclear factor-kappaB (NF-κB), induce the transcriptional expressions and release of massive inflammatory mediators, and promote the cascade amplification of inflammation, and form a ‘waterfall’ reaction of inflammation in the lung, leading to the occurrence of ALI [4,5]. Pan et al showed that Interleukin-35 (IL-35) improved acute lung

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