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ResearchIn-Press PreviewInflammation Open Access | 10.1172/jci.insight.155968

A20 and the non-canonical NF-κB pathway are key regulators of neutrophil recruitment during fetal ontogeny

Ina Rohwedder,1 Lou Martha Wackerbarth,1 Kristina Heinig,1 Annamaria Ballweg,1 Johannes Altstätter,1 Myriam Ripphahn,1 Claudia Nussbaum,2 Melanie Salvermoser,1 Susanne Bierschenk,1 Tobias Straub,3 Matthias Gunzer,4 Marc Schmidt-Supprian,5 Thomas Kolben,6 Christian Schulz,7 Averil Ma,8 Barbara Walzog,1 Matthias Heinig,9 and Markus Sperandio1

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

Find articles by Nussbaum, C. in: JCI | PubMed | Google Scholar

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

Find articles by Straub, T. in: JCI | PubMed | Google Scholar

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

Find articles by Schmidt-Supprian, M. in: JCI | PubMed | Google Scholar

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

Find articles by Kolben, T. in: JCI | PubMed | Google Scholar

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

Find articles by Schulz, C. in: JCI | PubMed | Google Scholar

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

1Institute of Cardiovascular Physiology and Pathophysiology, LMU Munich, Munich, Germany

2Department of Pediatrics, LMU Munich, Munich, Germany

3Core Facility Bioinformatics, BMC, LMU Munich, Munich, Germany

4Institute for Experimental Immunology and Imaging, University of Duisburg-Essen, Essen, Germany

5Department of Hematology and Obsterics, LMU Munich, Munich, Germany

6Department of Gynecology and Obstetrics, LMU Munich, Munich, Germany

7Department of Cardiology, LMU Munich, Munich, Germany

8Department of Medicine, UCSF, San Francisco, United States of America

9Institute for Computational Biology, Helmholtz Center Munich, Munich, Germany

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

Published January 12, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.155968.
Copyright © 2023, Rohwedder 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 January 12, 2023 - Version history
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Abstract

Newborns are at high risk of developing neonatal sepsis, particularly if born prematurely. This has been linked to divergent requirements the immune system has to fulfill during intrauterine compared to extrauterine life. By transcriptomic analysis of fetal and adult neutrophils we set out to shed new light on the molecular mechanisms of neutrophil maturation and functional adaption during fetal ontogeny. We identified an accumulation of differentially regulated genes within the non-canonical NF-κB signaling pathway accompanied by constitutive nuclear localization of RelB and increased surface expression of TNFRII in fetal neutrophils as well as elevated levels of LT-α in fetal serum. Furthermore, we found strong upregulation of the negative inflammatory regulator A20 (Tnfaip3) in fetal neutrophils, which was accompanied by a pronounced downregulation of the canonical NF-κB pathway. Functionally, overexpressing A20 in Hoxb8 cells led to reduced adhesion of these neutrophil-like cells under flow. Conversely, mice with a neutrophil specific A20 deletion displayed increased inflammation in vivo. Taken together, we have uncovered constitutive activation of the non-canonical NF-κB pathway with concomitant upregulation of A20 in fetal neutrophils. This offers perfect adaption of neutrophil function during intrauterine fetal life, but also restricts appropriate immune responses particularly in prematurely born infants.

Graphical Abstract
graphical abstract
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  • Version 1 (January 12, 2023): In-Press Preview
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