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

Furlong-Silva, Julio, Cross, Stephen D, Marriott, Amy E, Pionnier, Nicolas ORCID: https://orcid.org/0000-0002-2379-4945, Archer, John, Steven, Andrew, Merker, Stefan Schulte, Mack, Matthias, Hong, Young-Kwon, Taylor, Mark J and Turner, Joseph D (2021) Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis. Journal of Clinical Investigation, 131 (5). e140853. ISSN 0021-9738

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Official URL: https://www.jci.org/articles/view/140853

Abstract

Lymphatic filariasis is the major global cause of nonhereditary lymphedema. We demonstrate that the filarial nematode Brugia malayi induced lymphatic remodeling 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, the interleukin-4 receptor, and recruitment of C-C chemokine receptor-2–positive monocytes and alternatively activated macrophages with a prolymphangiogenic 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 prolymphangiogenic macrophage development. Doxycycline treatment impeded monocyte recruitment, inhibited polarization of alternatively activated macrophages, and suppressed T cell adaptive immune responses following infection. Our results determine a mechanism of action for the antimorbidity effects of doxycycline in filariasis and support clinical evaluation of second-generation tetracyclines as affordable, safe therapeutics for lymphedemas of chronic inflammatory origin.

Item Type:	Article (Article)
Peer-reviewed:	Yes
Date Deposited:	01 Apr 2022 12:58
Publisher:	American Society for Clinical Investigation
Additional Information:	This is an open access article published in the Journal of Clinical Investigation by American Society for Clinical Investigation.
Divisions:	Faculties > Science and Engineering
Subject terms:	BRUGIA-PAHANGI, DOUBLE-BLIND, GROWTH FACTOR-A, INFECTIONS, Life Sciences & Biomedicine, LYMPHEDEMA, MACROFILARICIDAL ACTIVITY, MACROPHAGES, Medicine, Research & Experimental, ONCHOCERCIASIS, POLARIZATION, Research & Experimental Medicine, Science & Technology, WUCHERERIA-BANCROFTI, Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, GROWTH FACTOR-A, WUCHERERIA-BANCROFTI, MACROFILARICIDAL ACTIVITY, BRUGIA-PAHANGI, DOUBLE-BLIND, MACROPHAGES, INFECTIONS, LYMPHEDEMA, ONCHOCERCIASIS, POLARIZATION, T-Lymphocytes, Monocytes, Animals, Mice, Inbred BALB C, Mice, Knockout, Mice, Brugia malayi, Elephantiasis, Filarial, Tetracyclines, Receptors, Interleukin-4, Cell Movement, Lymphangiogenesis, Male, Adaptive Immunity, Infectious disease, Inflammation, Lymph, Parasitology, Th2 response, Adaptive Immunity, Animals, Brugia malayi, Cell Movement, Elephantiasis, Filarial, Lymphangiogenesis, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Monocytes, Receptors, Interleukin-4, T-Lymphocytes, Tetracyclines, 11 Medical and Health Sciences, Immunology
URI:	https://e-space.mmu.ac.uk/id/eprint/629456
DOI:	https://doi.org/10.1172/JCI140853
ISSN	0021-9738
e-ISSN	1558-8238

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