Background and aims Diffuse alveolar haemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (miR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. The purpose of this study was to examine the role of miR-155 in the development of DAH in pristane-induced lupus using miR-155-knockout (miR-155-/-) mice and miR-155 antagomir to silence miR-155.
Methods DAH was induced by an intraperitoneal injection of 0.5 mL of pristane. MiR-155 antagomir was intravenously administrated to silence miR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analysed using Ingenuity Pathway Analysis. Real time q-PCR was used for single validation. Luciferase reporter assay and RNA-Ago2 immunoprecipitation were performed for target validation.
Results MiR-155 expression was significantly increased in the development of DAH. Disease progression was reduced in miR-155-/- mice and by in vivo silencing of miR-155 using miR-155 antagomir. MiR-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways, and reduced the expression of pro-inflammatory cytokines. Several negative regulators of nuclear factor (NF)-κB signalling were inhibited by pristane, and were re-activated in miR-155-/- mice. In particular, the anti-inflammatory factor peroxisome proliferator-activated receptor-α was identified as a direct target of miR-155.
Conclusions MiR-155 promotes pristane-induced lung inflammation. MiR-155 contributes to ectopic activation of NF-κB signalling pathways by targeting multiple negative regulators. MiR-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
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