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 1

Filarial lymphatic infection induces persistent lymphatic pathology.

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Filarial lymphatic infection induces persistent lymphatic pathology. (A)...
(A) Schematic of hind-limb filarial infection model. (B) Representative images of in vitro (left panel) or intralymphatic Alexa Fluor 546–labeled (AF546) BmL3 larvae in C57BL/6J Prox-1GFP mice, 1 dpi. Scale bars: 20 μm. (C) Representative PDE intravital images of sham-infected and BmL3-infected C57BL/6J mice, 14 dpi. (D) Quantified aberrant lymphatics from PDE imaging (n = 10 sham, n = 8 BmL3). (E) Representative epifluorescence micrographs of dermal lymphatics and (F) average dermal lymphatic vessel aperture in Prox-1GFP mice 14 dpi (n = 3 Sham, n = 4 BmL3). Scale bars: 200 μm. (G) Quantified hind-limb ICG dye retention from PDE imaging expressed as a ratio of fluorescence in the right (R, uninfected) vs. the left (L, infected) hind limb (n = 10 sham, n = 8 BmL3). (H) Evan’s blue left-hind-limb dermal retention (n = 9 sham, n = 8 BmL3). (I) Aberrant lymphatics and (J) hind-limb ICG retention comparing 2- and 16-week-old infections (n = 15 sham, n = 4 BmL3 at 2 weeks after infection, n = 4 at 16 weeks after infection). Histograms show the mean ± SEM. Data were pooled from 2–3 individual experiments (D and G–J) or 1 experiment (F). **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test (D and F–I) or 1-way ANOVA with Tukey’s multiple-comparison post hoc test (J). NS, not significant.