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 mirn23a, 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. Mirn23a(-/-) 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 mirn23a loss modulating immune cell polarization, we assayed syngeneic tumor growth in wild-type and mirn23a(-/-) mice. Consistent with the increased anti-inflammatory/immunosuppressive phenotype in vitro, mirn23a(-/-) mice inoculated with syngeneic tumor cells had worse outcomes compared with wild-type mice. Coinjecting tumor cells with mirn23a(-/-) BMDMs into wild-type mice phenocopied tumor growth in mirn23a(-/-) mice, supporting a critical role for mirn23a miRNAs in macrophage-mediated tumor immunity. Our data demonstrate that mirn23a regulates M1/M2 polarization and suggests that manipulation of mirn23a miRNA can be used to direct macrophage polarization to drive a desired immune response.

Automated summary

The miRNA cluster mirn23a regulates macrophage polarization, with mirn23a(-/-) mice showing worse outcomes in tumor growth experiments, indicating a critical role in tumor immunity. Manipulation of mirn23a miRNA can be used to direct macrophage polarization for desired immune responses.