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 3

Filaria-associated lymphatic pathology is dependent on type 2 adaptive immunity.

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Filaria-associated lymphatic pathology is dependent on type 2 adaptive i...
(A) Representative PDE intravital images and (B) aberrant lymphatic quantification of WT BALB/c and SCID mice at 2 and 5 weeks postinfection (wpi) (n = 8 WT sham, n = 10 WT BmL3 at 2 wpi and 5 wpi, n = 5 SCID sham, n = 4 SCID BmL3 at 2 wpi, n = 10 SCID BmL3 at 5 wpi). (C) Hind-limb ICG dye retention and (D) Evan’s blue left-hind-limb dermal retention in WT and SCID mice, 14 dpi (n = 7 WT sham, n = 14 WT BmL3, n = 5 SCID sham, n = 4 SCID BmL3). (E) Representative flow cytometry plots and (F) quantified cytokine production within sdLN CD4+ T cells from C57BL/6J mice, 14 dpi (n = 12 sham, n = 13 BmL3). Data are cytokine-expressing cells as a proportion of total CD4+ T cells. Histograms show the mean ± SEM. Data were pooled from 2 individual experiments (B and F) or a single experiment (D). *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison post hoc test between marked groups. NS, not significant.