Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor–mediated lymphangiogenesis
Julio Furlong-Silva, … , Mark J. Taylor, Joseph D. Turner
Julio Furlong-Silva, … , Mark J. Taylor, Joseph D. Turner
Published January 12, 2021
Citation Information: J Clin Invest. 2021;131(5):e140853. https://doi.org/10.1172/JCI140853.
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Research Article Infectious disease Inflammation

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

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.

Authors

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

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Figure 10

Doxycycline inhibits LEC proliferation directly and via impairment of type 2 or filaria-conditioned prolymphangiogenic MΦs.

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Doxycycline inhibits LEC proliferation directly and via impairment of ty...
(A) BEC and LEC 9-day proliferation tracking following stimulation with 2 ng/mL VEGF, with or without 10 or 20 μM doxycycline. Data are fold-changes from initial BEC and LEC confluence. (B) Representative images of BEC and LEC confluence at endpoint. Scale bar: 500 μm. (C) Schematic of MΦ-LEC coculture indicating where doxycycline was added. (D) LEC enumeration following coculture with MΦs preconditioned with rIL-4+rIL-13, rIL-4+rIL-13+BmL3, or BmL3 extract (BmL3E) with or without 10 μM doxycycline. (E) LEC enumeration following coculture with MΦs preconditioned with BmL3E with or without 10 μM doxycycline. Histograms show the mean ± SEM. Data were derived from a single experiment (A) or pooled from 2 individual experiments (D and E). *P < 0.05, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison post hoc test.