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ResearchIn-Press PreviewInflammationReproductive biology Open Access | 10.1172/JCI181839

TET3-overexpressing macrophages promote endometriosis

Haining Lv,1 Beibei Liu,1 Yangyang Dai,1 Feng Li,1 Stefania Bellone,1 Yuping Zhou,1 Ramanaiah Mamillapalli,1 Dejian Zhao,2 Muthukumaran Venkatachalapathy,3 Yali Hu,4 Gordon G. Carmichael,5 Da Li,1 Hugh S. Taylor,1 and Yingqun Huang1

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

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1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Liu, B. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Dai, Y. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Li, F. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Bellone, S. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Zhou, Y. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Mamillapalli, R. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Zhao, D. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Venkatachalapathy, M. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Hu, Y. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Carmichael, G. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Li, D. in: JCI | PubMed | Google Scholar |

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Taylor, H. in: JCI | PubMed | Google Scholar

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

2Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

3Department of Chemistry, Yale University, New Haven, United States of America

4Center for Reproductive Medicine and Obstetrics and Gynecology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

5Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, American Samoa

Find articles by Huang, Y. in: JCI | PubMed | Google Scholar |

Published August 14, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI181839.
Copyright © 2024, Lv et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 14, 2024 - Version history
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Abstract

Endometriosis is a debilitating, chronic inflammatory disease affecting ~10% of reproductive age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we reported identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We showed that factors from the disease microenvironment upregulated TET3 expression transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated pro-inflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival, hence vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation both in human and mouse macrophages. This degradation was dependent on a VHL E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.

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