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

Austin Boucher, Nathan Klopfenstein, William Morgan Hallas, Jennifer Skibbe, Andrew Appert, Seok Hee Jang, Kirthi Pulakanti, Sridhar Rao, Karen D. Cowden Dahl and Richard Dahl
J Immunol February 1, 2021, 206 (3) 540-553; DOI: https://doi.org/10.4049/jimmunol.1901277
Austin Boucher
*Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;
†Harper Cancer Research Institute, South Bend, IN 46617;
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Nathan Klopfenstein
†Harper Cancer Research Institute, South Bend, IN 46617;
‡Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617;
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William Morgan Hallas
†Harper Cancer Research Institute, South Bend, IN 46617;
§Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
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Jennifer Skibbe
†Harper Cancer Research Institute, South Bend, IN 46617;
‡Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617;
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Andrew Appert
*Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;
†Harper Cancer Research Institute, South Bend, IN 46617;
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Seok Hee Jang
*Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;
†Harper Cancer Research Institute, South Bend, IN 46617;
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Kirthi Pulakanti
¶Blood Research Institute, Versiti, Milwaukee, WI 53226;
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Sridhar Rao
¶Blood Research Institute, Versiti, Milwaukee, WI 53226;
‖Department of Cell Biology, Medical College of Wisconsin, Milwaukee, WI 53226;
#Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and
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Karen D. Cowden Dahl
†Harper Cancer Research Institute, South Bend, IN 46617;
§Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
**Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN 46617
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Richard Dahl
*Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;
†Harper Cancer Research Institute, South Bend, IN 46617;
‡Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617;
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Key Points

  • mirn23a miRNAs repress inflammatory signaling in myeloid progenitors.

  • mirn23a−/− macrophages have enhanced M2 polarization and decreased responses to LPS.

  • mirn23a−/− macrophages enhance the growth of syngeneic tumors in vivo.

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.

Footnotes

  • This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases DK109051 (to R.D.), the Ralph W. and Grace M. Showalter Research Trust Fund (to R.D.), the Indiana Clinical and Translational Sciences Institute (to R.D.), National Cancer Institute CA204231 (to S.R.), the Walther Cancer Foundation Interdisciplinary Interface Training Program (to A.B.), and the Research Like a Champion Program, University of Notre Dame (to A.B.). This work was also supported by the Indiana University School of Medicine South Bend Imaging and Flow Cytometry Core Facility.

  • The sequences presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession numbers GSE160214 and GSE159762.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    ACK
    ammonium–chloride–potassium
    BMDM
    bone marrow–derived macrophage
    GSEA
    Gene Set Enrichment Analysis
    HSPC
    hematopoietic stem and progenitor cell
    iNOS
    inducible NO synthase
    IPA
    Ingenuity Pathway Analysis
    LLC
    Lewis lung carcinoma
    miRNA
    microRNA
    MSCV
    murine stem cell virus
    qPCR
    quantitative PCR
    qRT-PCR
    quantitative RT-PCR
    RNA-seq
    RNA sequencing
    TAM
    tumor-associated macrophage.

  • Received October 23, 2019.
  • Accepted November 17, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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The miR-23a∼27a∼24-2 microRNA Cluster Promotes Inflammatory Polarization of Macrophages
Austin Boucher, Nathan Klopfenstein, William Morgan Hallas, Jennifer Skibbe, Andrew Appert, Seok Hee Jang, Kirthi Pulakanti, Sridhar Rao, Karen D. Cowden Dahl, Richard Dahl
The Journal of Immunology February 1, 2021, 206 (3) 540-553; DOI: 10.4049/jimmunol.1901277

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The miR-23a∼27a∼24-2 microRNA Cluster Promotes Inflammatory Polarization of Macrophages
Austin Boucher, Nathan Klopfenstein, William Morgan Hallas, Jennifer Skibbe, Andrew Appert, Seok Hee Jang, Kirthi Pulakanti, Sridhar Rao, Karen D. Cowden Dahl, Richard Dahl
The Journal of Immunology February 1, 2021, 206 (3) 540-553; DOI: 10.4049/jimmunol.1901277
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