title: In Vivo Therapeutic Success of MicroRNA-155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Xiao
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.affiliation: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Qu
authors.affiliation: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xinfang
authors.initials: X
authors.lastname: Huang
authors.affiliation: Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Tang
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, and Cincinnati VA Medical Center, Cincinnati, Ohio.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Renji Hospital, Institute of Health Sciences of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, China, and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D007166:Immunosuppressive Agents / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000633:toxicity
chemical_list: D007166:Immunosuppressive Agents; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016328:NF-kappa B; D009841:Oligonucleotides; D013729:Terpenes; C009042:pristane