Regulation of monocyte functional heterogeneity by miR-146a

Monocytes and their lineage descendants serve as a central defense system against infection and injury but if uncontrolled can also promote an excessive pathological inflammatory response. Therefore a current research goal is to understand how the organism controls the number and function of monocytes and how these variables can be tailored in therapy. Considering the evidence that monocytes are heterogeneous and exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6Chi and Ly-6Clo) and human (CD14hi and CD14lo CD16+) monocyte subsets. The single miRNA was found to significantly control the amplitude of the Ly-6Chi monocyte response during inflammatory challenge whereas it did not affect Ly-6Clo cells. miR-146a–mediated regulation was cell-intrinsic and depended on Relb, a member of the non-canonical NF-κB/Rel family, which is identified here as a novel miR-146a target. These observations provide novel mechanistic insights into the molecular events that regulate monocyte functional heterogeneity and identify therapeutic targets that can influence the quality and quantity of monocyte responses. 4 samples of splenic Ly-6Chi monocytes, 4 samples of splenic Ly-6Clo monocytes; both isolated from C57BL/6 mice. Each sample was generated by fluorecsence activated cell sorting from the pooled spleens of 10 mice.