Abstract
Recent evidence showed that microRNA-7 (miR-7) played an important role in the pathologies of lung-related diseases. However, the potential role of miR-7 in acute lung injury (ALI) still remains poorly understood. Here, we assessed the effect of miR-7 deficiency on the pathology of ALI. We, first, found that the expression of miR-7 was upregulated in lung tissue in murine LPS-induced ALI model. Notably, we generated miR-7 knock down mice by using miRNA-Sponge technique and found that miR-7 deficiency could ameliorate the pathologies of lung as evidenced by accelerated body weight recovery, reduced level of bronchoalveolar lavage (BAL) proinflammatory cytokines and decreased number of BAL cells in ALI mice. Moreover, the proportion and number of various immune cells in BAL, including innate immune cell F4/80+ macrophages, γδT cells, NK1.1+ T cells, and CD11c+DCs, as well as adaptive immune cell CD4+ T cells and CD8+ T cells, also significantly changed, respectively. Mechanistic evidence showed that KLF4, a target molecule of miR-7, was upregulated in lung tissues in ALI model, accompanied by altered transduction of NF-κB, AKT, and ERK pathway. These data provided a previously unknown role of miR-7 in pathology of ALI, which could ultimately aid the understanding of development of ALI and the development of new therapeutic strategies against clinical inflammatory lung diseases.
Highlights
The development of acute lung injury (ALI), a clinically important complication of severe ALI in humans is a complex process, including a series of integrated steps, including the infiltration of innate and adaptive immune cells and the conversion in the balance of proinflammatory and anti-inflammatory cytokines [1,2,3,4]
We further detected the expression of miR-7 in lung tissues of miR-7 KD (miR-7KD) mice using in situ hybridization and obtained similar results (Figure 1E)
The relative expression of miR-7 in other various organs and tissues in miR-7KD mice decreased significantly (Figure S2 in Supplementary Material, p < 0.05). These results demonstrated that miR-7KD mice were successfully generated using miRNA Sponge (miR-SP) Technology
Summary
The development of acute lung injury (ALI), a clinically important complication of severe ALI in humans is a complex process, including a series of integrated steps, including the infiltration of innate and adaptive immune cells and the conversion in the balance of proinflammatory and anti-inflammatory cytokines [1,2,3,4]. Recent evidence showed that microRNAs (miRNAs), small endogenous RNAs of 21–25 nucleotides capable of guiding the post-transcriptional silencing of their target mRNAs through base pairing encompassing mature mRNA 3′UTR [5, 6], played an important regulatory role in the development of ALI [7, 8]. Xu et al [10] found that miR-17 expression was downregulated during development of ALI, accompanied by upregulation of its target gene FoxA1, and may play an important role in ALI. MicroRNA-7 Deficiency Ameliorates AIL macrophages (Mφ) induced expansion of Tregs [11]. These studies indicated that miRNAs might be a potential candidate for the therapy against ALI. Further study on the possible role of distinct miRNA molecules in the development of ALI could benefit the understanding of pathology of ALI and be valuable for the development of novel clinical therapeutic strategies
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