In Vivo Therapeutic Success of MicroRNA-155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage

Arthritis Rheumatol. 2016 Apr;68(4):953-64. doi: 10.1002/art.39485.


Objective: Diffuse alveolar hemorrhage (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. Recent studies have revealed a pathogenic role of miR-155 in various autoimmune disorders. 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. MicroRNA-155 antagomir was administered intravenously to silence miR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real-time quantitative polymerase chain reaction analysis was used for single-gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation.

Results: MicroRNA-155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR-155(-/-) mice as well as by in vivo silencing of miR-155 using a miR-155 antagomir. MicroRNA-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF-κB signaling were inhibited by pristane and were reactivated in miR-155(-/-) mice. In particular, the antiinflammatory factor peroxisome proliferator-activated receptor α was identified as a direct target of miR-155.

Conclusion: MicroRNA-155 promotes pristane-induced lung inflammation. It contributes to ectopic activation of NF-κB signaling pathways by targeting multiple negative regulators. MicroRNA-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gene Expression Regulation
  • Hemorrhage / drug therapy*
  • Hemorrhage / etiology
  • Hemorrhage / genetics
  • Immunosuppressive Agents / toxicity
  • Lung / drug effects
  • Lung / metabolism
  • Lung Diseases / drug therapy*
  • Lung Diseases / etiology
  • Lung Diseases / genetics
  • Lupus Erythematosus, Systemic / chemically induced
  • Lupus Erythematosus, Systemic / complications
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / antagonists & inhibitors*
  • MicroRNAs / genetics
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Oligonucleotides / pharmacology
  • Oligonucleotides / therapeutic use*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Terpenes / toxicity


  • Immunosuppressive Agents
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • NF-kappa B
  • Oligonucleotides
  • Terpenes
  • pristane