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ResearchIn-Press PreviewInfectious diseaseInflammation Free access | 10.1172/JCI140853

Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis

Julio Furlong-Silva,1 Stephen D. Cross,1 Amy E. Marriott,1 Nicolas Pionnier,1 John Archer,1 Andrew Steven,1 Stefan Schulte-Merker,3 Matthias Mack,4 Young-Kwon Hong,5 Mark J. Taylor,1 and Joseph D. Turner1

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

Find articles by Pionnier, N. in: JCI | PubMed | Google Scholar |

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

Find articles by Schulte-Merker, S. in: JCI | PubMed | Google Scholar |

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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

1Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

2Centre for Drugs & Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Livrerpool, United Kingdom

3Faculty of Medicine, Institute for Cardiovascular Organogenesis and Regeneration, Utrecht, United Kingdom

4Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

5Department of Surgery, University of Southern California, Los Angeles, United States of America

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

Published January 12, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI140853.
Copyright © 2021, American Society for Clinical Investigation
Published January 12, 2021 - Version history
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Abstract

Lymphatic filariasis is the major global cause of non-hereditary lymphoedema. We demonstrate the filarial nematode, Brugia malayi, induces lymphatic remodelling and impaired lymphatic drainage following parasitism of limb lymphatics in a mouse model. Lymphatic insufficiency was associated with elevated circulating lymphangiogenic mediators, including vascular endothelial growth factor C. Lymphatic insufficiency was dependent on type-2 adaptive immunity, interleukin-4 receptor, recruitment of C-C chemokine receptor-2 monocytes and alternatively-activated macrophages with pro-lymphangiogenic phenotype. Oral treatments with second-generation tetracyclines improved lymphatic function, while other classes of antibiotic had no significant effect. Second-generation tetracyclines directly targeted lymphatic endothelial cell proliferation and modified type-2 pro-lymphangiogenic macrophage development. Doxycycline treatment impeded monocyte recruitment, inhibited polarisation of alternatively-activated macrophages and suppressed T cell adaptive immune responses following infection. Our results determine a mechanism-of-action for the anti-morbidity effects of doxycycline in filariasis and supports clinical evaluation of second-generation tetracyclines as affordable, safe therapeutics for lymphoedemas of chronic inflammatory origin.

Graphical Abstract
graphical abstract
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  • Version 1 (January 12, 2021): In-Press Preview
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