PMID- 33328213 OWN - NLM STAT- MEDLINE DCOM- 20210802 LR - 20220202 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 206 IP - 3 DP - 2021 Feb 1 TI - The miR-23a approximately 27a approximately 24-2 microRNA Cluster Promotes Inflammatory Polarization of Macrophages. PG - 540-553 LID - 10.4049/jimmunol.1901277 [doi] AB - 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. CI - Copyright (c) 2021 by The American Association of Immunologists, Inc. FAU - Boucher, Austin AU - Boucher A AD - Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556. AD - Harper Cancer Research Institute, South Bend, IN 46617. FAU - Klopfenstein, Nathan AU - Klopfenstein N AD - Harper Cancer Research Institute, South Bend, IN 46617. AD - Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617. FAU - Hallas, William Morgan AU - Hallas WM AD - Harper Cancer Research Institute, South Bend, IN 46617. AD - Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. FAU - Skibbe, Jennifer AU - Skibbe J AUID- ORCID: 0000-0002-7220-3769 AD - Harper Cancer Research Institute, South Bend, IN 46617. AD - Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617. FAU - Appert, Andrew AU - Appert A AD - Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556. AD - Harper Cancer Research Institute, South Bend, IN 46617. FAU - Jang, Seok Hee AU - Jang SH AD - Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556. AD - Harper Cancer Research Institute, South Bend, IN 46617. FAU - Pulakanti, Kirthi AU - Pulakanti K AUID- ORCID: 0000-0003-1167-8493 AD - Blood Research Institute, Versiti, Milwaukee, WI 53226. FAU - Rao, Sridhar AU - Rao S AUID- ORCID: 0000-0003-2688-9541 AD - Blood Research Institute, Versiti, Milwaukee, WI 53226. AD - Department of Cell Biology, Medical College of Wisconsin, Milwaukee, WI 53226. AD - Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and. FAU - Cowden Dahl, Karen D AU - Cowden Dahl KD AUID- ORCID: 0000-0002-9604-3026 AD - Harper Cancer Research Institute, South Bend, IN 46617. AD - Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. AD - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN 46617. FAU - Dahl, Richard AU - Dahl R AUID- ORCID: 0000-0002-6341-5604 AD - Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556; richdahl@iupui.edu. AD - Harper Cancer Research Institute, South Bend, IN 46617. AD - Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617. LA - eng GR - R01 CA204231/CA/NCI NIH HHS/United States GR - R01 DK109051/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201216 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Cytokines) RN - 0 (MicroRNAs) RN - 0 (Mirn23b microRNA, mouse) RN - 0 (Mirn24 microRNA, mouse) RN - 0 (Mirn27 microRNA, mouse) SB - IM MH - Animals MH - Cell Differentiation/genetics MH - Cell Line, Tumor MH - Cytokines/metabolism MH - Female MH - Humans MH - Inflammation/*genetics MH - Macrophages/*immunology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - MicroRNAs/*genetics MH - Neoplasms, Experimental MH - Ovarian Neoplasms/*immunology MH - Th1 Cells/immunology MH - Tumor Burden MH - Tumor-Associated Macrophages/*immunology PMC - PMC7855803 MID - NIHMS1648962 COIS- Disclosures The authors have no financial conflicts of interest. EDAT- 2020/12/18 06:00 MHDA- 2021/08/03 06:00 PMCR- 2022/02/01 CRDT- 2020/12/17 05:38 PHST- 2019/10/23 00:00 [received] PHST- 2020/11/17 00:00 [accepted] PHST- 2020/12/18 06:00 [pubmed] PHST- 2021/08/03 06:00 [medline] PHST- 2020/12/17 05:38 [entrez] PHST- 2022/02/01 00:00 [pmc-release] AID - jimmunol.1901277 [pii] AID - 10.4049/jimmunol.1901277 [doi] PST - ppublish SO - J Immunol. 2021 Feb 1;206(3):540-553. doi: 10.4049/jimmunol.1901277. Epub 2020 Dec 16.