miR-511-3p Modulates Genetic Programs of Tumor-Associated Macrophages

SummaryExpression of the mannose receptor (MRC1/CD206) identifies macrophage subtypes, such as alternatively activated macrophages (AAMs) and M2-polarized tumor-associated macrophages (TAMs), which are endowed with tissue-remodeling, proangiogenic, and protumoral activity. However, the significance of MRC1 expression for TAM's protumoral activity is unclear. Here, we describe and characterize miR-511-3p, an intronic microRNA (miRNA) encoded by both mouse and human MRC1 genes. By using sensitive miRNA reporter vectors, we demonstrate robust expression and bioactivity of miR-511-3p in MRC1+ AAMs and TAMs. Unexpectedly, enforced expression of miR-511-3p tuned down the protumoral gene signature of MRC1+ TAMs and inhibited tumor growth. Our findings suggest that transcriptional activation of Mrc1 in TAMs evokes a genetic program orchestrated by miR-511-3p, which limits rather than enhances their protumoral functions. Besides uncovering a role for MRC1 as gatekeeper of TAM's protumoral genetic programs, these observations suggest that endogenous miRNAs may operate to establish thresholds for inflammatory cell activation in tumors.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The active strand of miR-511 in both mouse and human precursor is miR-511-3p ► miR-511-3p is coregulated with the mannose receptor (Mrc1) gene ► miR-511-3p is highly active in MRC1+ alternatively activated and tumor macrophages ► The protumoral gene signature of MRC1+ tumor macrophages is tuned down by miR-511-3p