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 11

Doxycycline ameliorates filarial lymphatic pathology by modulation of IL-4R–dependent inflammatory lymphangiogenesis.

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Doxycycline ameliorates filarial lymphatic pathology by modulation of IL...
(A) Immune cell populations from sdLNs and surrounding lymphatics from C57BL/6J sham- or BmL3-infected mice treated with vehicle or 40 mg/kg doxycycline twice daily, 14 dpi. (B) Representative flow cytometry plots and (C) MФ expression of RELM-α (n = 6 sham and BmL3+Veh, n = 5 BmL3+doxycycline). Cells were gated on live CD11b+MHCII+F4/80+ cells. Data are RELM-α+ MΦs as a proportion of total MΦs. (D) Proteomic array of lymphangiogenic molecules in 72-hour cell cultures derived from sdLNs and lymphatic tissues, 14 dpi. Heatmap orange and red depict increasing fold-change compared with the mean of sham-infected mice. (E) Lymphangiogenic molecules attaining statistical significance; data plotted per mouse (n = 3 sham, BmL3, and BmL3+doxycycline). (F) Proteomic array of cytokine levels in splenocyte cultures 72 hours after polyclonal restimulation with anti-CD3/anti-CD28 antibodies. Heatmap orange and red depict increasing fold-change compared with the mean of sham-infected mice. (G) Cytokine concentrations attaining statistical significance, grouped under type of adaptive immune response; data plotted per mouse (n = 5 sham, BmL3, and BmL3+doxycycline). Histograms show the mean ± SEM. Data were pooled from 2 individual experiments (A and C) or derived from a single experiment (E and G). *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparison post hoc test. NS, not significant.