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ResearchIn-Press PreviewCell biologyVascular biology Open Access | 10.1172/JCI203265

Efferocytosis activates a DNMT3A-mediated oxidized DNA repair pathway to enable tissue resolution

Kleopatra Avrampou,1 Santosh R. Sukka,1 David Ngai,1 Patrick Ampomah,1 Xiaobo Wang,1 George Kuriakose,1 Jacob Glass,2 Bernhard Dorweiler,3 Hanna Winter,4 Lars Maegdefessel,5 Hanrui Zhang,1 Aaron Viny,1 and Ira Tabas1

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Avrampou, K. in: PubMed | Google Scholar

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

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

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

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1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Ampomah, P. in: PubMed | Google Scholar

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Wang, X. in: PubMed | Google Scholar |

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

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

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Glass, J. in: PubMed | Google Scholar

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

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

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

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

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Maegdefessel, L. in: PubMed | Google Scholar |

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

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

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Viny, A. in: PubMed | Google Scholar |

1Department of Medicine, Columbia University Irving Medical Center, New York, United States of America

2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Vascular and Endovascular Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

4Institute of Molecular Vascular Medicine, TUM Klinikum, Technical University of Munich, Munich, Germany

5Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, United States of America

Find articles by Tabas, I. in: PubMed | Google Scholar |

Published July 21, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI203265.
Copyright © 2026, Avrampou 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 July 21, 2026 - Version history
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Abstract

Efferocytosis, the clearance of apoptotic cells by macrophages, promotes tissue resolution. Efficient resolution requires efferocytosis-induced macrophage proliferation (EIMP) to expand pro-resolving macrophages. Here, we show that efferocytosis activates base excision repair (BER) to remove 8-OHdG from DNA, enabling EIMP. Mechanistically, efferocytosis promotes poly(ADP-ribose) polymerase-1 (PARP1) chromatin binding and PARylation to facilitate DNA repair complex assembly, and increases nuclear MTH1/NUDT1, which hydrolyzes 8-OHdG. Both processes require DNA-methyltransferase-3A (DNMT3A), which is activated during efferocytosis. Using a model where dexamethasone-induced thymocyte apoptosis triggers efferocytosis-mediated thymic repair, we showed that DNMT3A is required for increases in nuclear PARP1/MTH1, oxidized DNA suppression, EIMP in thymic macrophages, and thymic repair. We next studied a human-relevant model of atherosclerosis regression, where efferocytosis drives protective lesional fibrous cap thickening. We compared WT mice with a model of DNMT3A-clonal hematopoiesis (CH), in which loss-of-function DNMT3A mutations promote atherosclerotic disease. Atherosclerosis regression in WT mice led to decreased nuclear 8-OHdG and increases in nuclear PARP1/MTH1 and EIMP in lesional macrophages and fibrous cap thickening, all of which were impaired in DNMT3A-CH regression. These findings reveal that efferocytosis initiates a BER pathway to allow macrophage proliferation for tissue resolution, with possible therapeutic relevance to atherosclerosis regression and DNMT3A-CH.

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Version history
  • Version 1 (July 21, 2026): In-Press Preview
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