Abstract
Silicosis is an incurable occupational disease associated with inflammation, fibroblast proliferation and the accumulation of extracellular matrix in lung tissues. The dysregulation of lncRNAs and miRNAs has been implicated in many complex diseases; however, the current understanding of their roles in fibrotic lung diseases, especially silicosis, remains limited. Our previous microRNA (miRNA, miR) microarray data have indicated decreased expression levels of miR-489 in lung tissues of silica-induced pulmonary fibrosis. Here, we further explored the role of miR-489 in a mouse model of silicosis. Interestingly, miR-489 levels were reduced in both macrophages that were exposed to silica and fibroblasts that were exposed to TGF-β1. Additionally, the overexpressed miR-489 carried out its anti-fibrotic role by attenuating inflammation and fibrotic progression in vivo. Our molecular study further demonstrated that miR-489 inhibited silica-induced pulmonary fibrosis primarily by repressing its target genes MyD88 and Smad3. Moreover, the up-regulated lncRNA cardiac hypertrophy-related factor (CHRF) reversed the inhibitory effect of miR-489 on MyD88 and Smad3 and then triggered the inflammation and fibrotic signaling pathways. Overall, our data indicate that the CHRF-miR-489-MyD88 Smad3 signaling axis exerts key functions in silica-induced pulmonary fibrosis and may represent a therapeutic target for silicosis.
Highlights
Silicosis, caused by the inhalation of crystalline silicon dioxide or silica, is one of the most severe occupational diseases[1,2]
Compared with the well-reported dysregulated miRNAs that participate in diseases, only a small portion of Long non-coding RNAs (lncRNAs) have been investigated regarding their functions in lung cancer, including MALAT116, H1917 and HOTAIR18, and even fewer have been recognized in pulmonary fibrosis
To confirm the change in the miR-489 level after treatment with silica that had been identified in our miRNA microarray data, we examined the expression levels of miR-489 in fibrotic lung tissues by using qRT-PCR analysis and confirmed that the miR-489 levels on days 7, 14, and 28 after silica injection were decreased compared with those in the day 28 saline group (Fig. 1D)
Summary
Silicosis, caused by the inhalation of crystalline silicon dioxide or silica, is one of the most severe occupational diseases[1,2]. MiR-199a-5p acts as an effector of TGF-βsignaling, regulates Caveolin-1 expression and participates in lung fibroblast activation processes[9] It remains largely unknown how miRNAs regulate pulmonary fibrosis, silicosis. A recent study has revealed that the long-intergenic non-coding RNAs (lincRNAs) MRAK088388 and MRAK081523 regulate N4bp[2] and Plxna[4] by acting as ceRNAs that sponge miR-29b-3p and let-7i-5p in bleomycin-induced pulmonary fibrosis[19]. This individual report highlights the urgent need to systematically identify aberrant lncRNAs and to clarify their general mechanism in pulmonary fibrosis. Our study indicates the potential of CHRF and miR-489 to be novel therapeutic targets for silicosis
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