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

Abstract

Expression 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.

Adaptive Immunity to Fungi

“…The MR can induce NF-kB activation and the production of IL-12, GM-CSF, IL-8, IL-1b, and IL-6 (Zhang et al 2004;Pietrella et al 2005;Taylor et al 2005;Tachado et al 2007). One caveat of studies with MR-deficient mice is that MRC1 expression is coregulated with the macrophage activating miRNA (miR-511-3p) (Squadrito et al 2012). Although the MR has been reported to induce Th17 cell differentiation of human T cells in response to C. albicans, memory and not naïve T cells were the major source of the IL-17 produced (Levitz 2009;van de Veerdonk et al 2009).…”

A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice

“…10 Recently, miR-511-3p, an miRNA encoded by the Mrc1 gene and thus associated with the macrophage subset with tissue remodeling function, has been shown to provide a negative feedback on protumoral genetic programs. 11 On the other hand, miRNAs can promote inflammation. miR-155 is upregulated by immune stimuli such as antigens, Toll-like receptor ligands, and inflammatory cytokines in cells of the innate and adaptive immune system.…”

miRNA in Macrophage Development and Function

“…miR-511-3p, an intronic miRNA, is encoded by both mouse and human MRC1 genes (83). Using reporter vector bioassay, miR-511-3p was noted to show high expression and activity in CD206 + TAMs (83). By targeting CD206 (MRC1), miRNA-511-3p plays a critical role as gatekeepers of the protumorigenic activity of TAMs.…”

“…In mouse models, a specific subset of TAMs that displays high expression of the mannose receptor (MRC1/CD206) and attenuated CD11c expression has been identified with high proangiogenic and tumorigenic activities (83). miR-511-3p, an intronic miRNA, is encoded by both mouse and human MRC1 genes (83). Using reporter vector bioassay, miR-511-3p was noted to show high expression and activity in CD206 + TAMs (83).…”

“…Cancer-related studies suggest the involvement of miRNAs in modulating response to TAM by directly acting on these macrophages and the precursors of these cells, including HSCs (82). In mouse models, a specific subset of TAMs that displays high expression of the mannose receptor (MRC1/CD206) and attenuated CD11c expression has been identified with high proangiogenic and tumorigenic activities (83). miR-511-3p, an intronic miRNA, is encoded by both mouse and human MRC1 genes (83).…”