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.