MicroRNA‐451 Down‐Regulates Neutrophil Chemotaxis via p38 MAPK

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. Conclusion These results suggest that miR‐451 suppresses neutrophil chemotaxis via p38 MAPK and is a potential target in the treatment of RA.