miR-451 downregulates neutrophil chemotaxis via p38 mitogen-activated protein kinase.

Abstract

Objective. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate the activities of target mRNAs and cellular processes. miR-451 is one of miRNAs conserved perfectly among vertebrates and regulates cell proliferation, invasion, and apoptosis in tumor. However, the role of miR-451 in autoimmune arthritis has been unknown. Our study was designed 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 (HCs). The role of miR-451 in neutrophil chemotaxis was evaluated in vivo and in vitro using neutrophils of mice. The regulation of p38 mitogen-activated protein kinase by miR-451 was assessed. Arthritis score and histology in SKG mice were examined by the administration of double-stranded miR-451. Results. miR-451 expression was lower in neutrophils isolated from patients with RA than in those from HCs. Systemic administration of miR-451 significantly disturbed the infiltration of neutrophils in air pouch model without affecting apoptosis of neutrophils. Overexpression of miR-451 significantly suppressed the migration of neutrophils to formyl-methionyl-leucyl-phenylalanine. We identified CPNE3 and Rab5a as direct targets of miR-451. Overexpression of miR-451 suppressed the phosphorylation of p38 mitogen-activated protein kinase (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 that miR-451 is a potential therapeutic target in the treatment of RA.