The miR-23a∼27a∼24-2 microRNA Cluster Promotes Inflammatory Polarization of Macrophages.

Macrophages are critical for regulating inflammatory responses. Environmental signals polarize macrophages to either a proinflammatory (M1) state or an anti-inflammatory (M2) state. We observed that the microRNA (miRNA) cluster , coding for miRs-23a, -27a, and -24-2, regulates mouse macrophage polarization. Gene expression analysis of mirn23a-deficient myeloid progenitors revealed a decrease in TLR and IFN signaling. bone marrow-derived macrophages (BMDMs) have an attenuated response to LPS, demonstrating an anti-inflammatory phenotype in mature cells. In vitro, mirn23a BMDMs have decreased M1 responses and an enhanced M2 responses. Overexpression of mirn23a has the opposite effect, enhancing M1 and inhibiting M2 gene expression. Interestingly, expression of mirn23a miRNAs goes down with inflammatory stimulation and up with anti-inflammatory stimulation, suggesting that its regulation prevents locking macrophages into polarized states. M2 polarization of tumor-associated macrophages (TAMs) correlates with poor outcome for many tumors, so to determine if there was a functional consequence of loss modulating immune cell polarization, we assayed syngeneic tumor growth in wild-type and mice. Consistent with the increased anti-inflammatory/immunosuppressive phenotype in vitro, mice inoculated with syngeneic tumor cells had worse outcomes compared with wild-type mice. Coinjecting tumor cells with BMDMs into wild-type mice phenocopied tumor growth in mice, supporting a critical role for miRNAs in macrophage-mediated tumor immunity. Our data demonstrate that regulates M1/M2 polarization and suggests that manipulation of miRNA can be used to direct macrophage polarization to drive a desired immune response.