title: MicroRNA-451 down-regulates neutrophil chemotaxis via p38 MAPK.
abstract: OBJECTIVE
  MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate the activity of target messenger RNAs (mRNAs) and cellular processes. MicroRNA-451 (miR-451) is one of the miRNAs that is conserved perfectly among vertebrates, and it regulates cell proliferation, invasion, and apoptosis in tumors. However, the role of miR-451 in autoimmune arthritis is unknown. This study was undertaken to identify the role of miR-451 in autoimmune arthritis.
  
  
  METHODS
  We compared the expression of miR-451 in neutrophils from patients with rheumatoid arthritis (RA) and healthy controls. We also evaluated the role of miR-451 in neutrophil chemotaxis in vivo and in vitro using murine neutrophils. The regulation of p38 MAPK by miR-451 was assessed. Double-stranded miR-451 was administered to SKG mice, the arthritis score was determined, and histologic examination was performed.
  
  
  RESULTS
  MicroRNA-451 expression in neutrophils isolated from patients with RA was lower than that in healthy controls. Systemic administration of miR-451 significantly disrupted the infiltration of neutrophils in an air-pouch model of local inflammation without affecting apoptosis of neutrophils. Overexpression of miR-451 significantly suppressed the migration of neutrophils to fMLP. We identified CPNE3 and Rab5a as direct targets of miR-451. Overexpression of miR-451 suppressed the phosphorylation of p38 MAPK via 14-3-3ζ, a known target of miR-451, and Rab5a. In SKG mice, miR-451 treatment reduced the severity of arthritis and the number of infiltrating cells.
  
  
  CONCLUSIONS
  These results suggest that miR-451 suppresses neutrophil chemotaxis via p38 MAPK and is a potential target in the treatment of RA.
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Murata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Furu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shibuya
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ito
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D012720:Severity of Illness Index; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D048051:p38 Mitogen-Activated Protein Kinases