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

Furlong-Silva, Julio, Cross, Stephen, Marriott, Amy, Pionnier, Nicolas ORCID: https://orcid.org/0000-0002-2379-4945, Archer, John, Steven, Andrew, Schulte-Merker, Stefan, Mack, Matthias, Hong, Young-Kwon, Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275 and Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476 (2021) 'Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis'. Journal of Clinical Investigation, Vol 131, Issue 5, e140853.

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Abstract

Lymphatic filariasis is the major global cause of non-hereditary lymphedema. 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 lymphedemas of chronic inflammatory origin.

Item Type:	Article
Subjects:	QS Anatomy > QS 18 Education QS Anatomy > QS 20.5 Research (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1172/JCI140853
Depositing User:	Cathy Waldron
Date Deposited:	14 Jan 2021 11:01
Last Modified:	03 Mar 2021 11:20
URI:	https://archive.lstmed.ac.uk/id/eprint/16662

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