Abstract
The nematodes Wuchereria bancrofti and Brugia spp. infect over 120 million people worldwide, causing lymphedema, elephantiasis and hydrocele, collectively known as lymphatic filariasis. Most infected individuals appear to be asymptomatic, but many exhibit sub-clinical manifestations including the lymphangiectasia that likely contributes to the development of lymphedema and elephantiasis. As adult worm excretory-secretory products (ES) do not directly activate lymphatic endothelial cells (LEC), we investigated the role of monocyte/macrophage-derived soluble factors in the development of filarial lymphatic pathology. We analyzed the production of IL-8, IL-6 and VEGF-A by peripheral blood mononuclear cells (PBMC) from naïve donors following stimulation with filarial ES products. ES-stimulated PBMCs produced significantly more IL-8, IL-6 and VEGF-A compared to cells cultured in medium alone; CD14+ monocytes appear to be the primary producers of IL-8 and VEGF-A, but not IL-6. Furthermore, IL-8, IL-6 and VEGF-A induced in vitro tubule formation in LEC Matrigel cultures. Matrigel plugs supplemented with IL-8, IL-6, VEGF-A, or with supernatants from ES-stimulated PBMCs and implanted in vivo stimulated lymphangiogenesis. Collectively, these data support the hypothesis that monocytes/macrophages exposed to filarial ES products may modulate lymphatic function through the secretion of soluble factors that stimulate the vessel growth associated with the pathogenesis of filarial disease.
Highlights
Lymphatic vessels (LVs) are important components of a system vital to the body’s maintenance that includes immune surveillance and fat absorption; the primary function of these vessels is to drain excess interstitial fluids and to prevent tissue swelling [1]
We evaluated the ability of Brugia excretory-secretory products (ES) products to induce the secretion of molecules known to exhibit lymphangiogenic potential in other in vivo and in vitro settings
Cells cultured with filarial ES products secreted significantly higher levels of IL-8, IL-6 and vascular endothelial growth factors (VEGF)-A compared to cells cultured in media alone (Fig. 1)
Summary
Lymphatic vessels (LVs) are important components of a system vital to the body’s maintenance that includes immune surveillance and fat absorption; the primary function of these vessels is to drain excess interstitial fluids and to prevent tissue swelling [1]. The majority of lymphatic pathology seen worldwide is associated with the filarial nematode parasites, Wuchereria bancrofti and Brugia malayi which cause lymphedema in millions of individuals. Lymphatic filariasis is an infection with varying degrees of clinical disease, where infected individuals can exhibit overt clinical symptoms such as lymphedema and hydrocele or be asymptomatic yet with microfilaremia. These asymptomatic microfilaremic individuals do not display any overt clinical manifestations, they do present with hidden sub-clinical complications [2,3] such as dilated and tortuous lymphatics [4,5], and scrotal lymphangiectasia in men [6,7]. It was demonstrated that children as young as three years of age can present with lymphangiectasia as measured by lymphoscintigraphy suggesting that sub-clinical pathology can occur at a very early age [11]
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