Faculty Collaboration Database

The miR-23a∼27a∼24-2 microRNA Cluster Promotes Inflammatory Polarization of Macrophages. J Immunol 2021 Feb 01;206(3):540-553

Date

12/18/2020

Pubmed ID

33328213

Pubmed Central ID

PMC7855803

DOI

10.4049/jimmunol.1901277

Scopus ID

2-s2.0-85099958710 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

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.

Author List

Boucher A, Klopfenstein N, Hallas WM, Skibbe J, Appert A, Jang SH, Pulakanti K, Rao S, Cowden Dahl KD, Dahl R

Author

Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Cell Line, Tumor
Cytokines
Female
Humans
Inflammation
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs
Neoplasms, Experimental
Ovarian Neoplasms
Th1 Cells
Tumor Burden