MicroRNA-181b Regulates ALX/FPR2 Receptor Expression and Proresolution Signaling in Human Macrophages

Regulatory mechanisms of ALX/FPR2, the lipoxin A4 receptor, expression have considerable relevance in inflammation resolution. Because microRNAs (miRs) are emerging as key players in inflammation resolution, here we examined microRNA-mediated regulation of ALX/FPR2 (lipoxin A4 receptor/formyl peptide receptor 2) expression. By matching data from bioinformatic algorithms, we found 27 miRs predicted to bind the 3′-UTR of ALX/FPR2. Among these, we selected miR-181b because of its link with inflammation. Using a luciferase reporter system, we assessed miR-181b binding to ALX/FPR2 3′-UTR. Consistent with this, miR-181b overexpression in human macrophages significantly down-regulated ALX/FPR2 protein levels (−25%), whereas miR-181b knockdown gave a significant increase in ALX/FPR2 (+60%). miR-181b levels decreased during monocyte to macrophage differentiation (−50%), whereas ALX/FPR2 expression increased significantly (+60%). miR-181b overexpression blunted lipoxin A4 (0.1–10 nm)- and resolvin D1 (0.01–10 nm)-stimulated phagocytic activity of macrophages. These results unravel novel regulatory mechanisms of ALX/FPR2 expression and ligand-evoked macrophages proresolution responses mediated by miR-181b, thus uncovering novel components of the endogenous inflammation resolution circuits. Background: The ALX/FPR2 receptor recognizes the proresolution mediators lipoxin A4 (LXA4) and resolvin (Rv) D1, thus modulating immune responses. Results: miR-181b binds to the 3′-UTR of the ALX/FPR2 gene, regulating its expression. mir-181b blunted LXA4- and RvD1-induced macrophage phagocytosis. Conclusion: miR-181b controls ALX/FPR2 expression. This mechanism modulates proresolution signals in macrophages. Significance: miR regulation of ALX/FPR2 expression may be exploited for innovative anti-inflammatory strategies.