Lymphatic Vascularisation and Involvement of Lyve-1+ Macrophages in the Human Onchocerca Nodule

Abstract

Onchocerciasis, caused by the filarial nematode Onchocerca volvulus, is a parasitic disease leading to debilitating skin disease and blindness, with major economic and social consequences. The pathology of onchocerciasis is principally considered to be a consequence of long-standing host inflammatory responses. In onchocerciasis a subcutaneous nodule is formed around the female worms, the core of which is a dense infiltrate of inflammatory cells in which microfilariae are released. It has been established that the formation of nodules is associated with angiogenesis. In this study, we show using specific markers of endothelium (CD31) and lymphatic endothelial cells (Lyve-1, Podoplanin) that not only angiogenesis but also lymphangiogenesis occurs within the nodule. 7% of the microfilariae could be found within the lymphatics, but none within blood vessels in these nodules, suggesting a possible route of migration for the larvae. The neovascularisation was associated with a particular pattern of angio/lymphangiogenic factors in nodules of onchocerciasis patients, characterized by the expression of CXCL12, CXCR4, VEGF-C, Angiopoietin-1 and Angiopoietin-2. Interestingly, a proportion of macrophages were found to be positive for Lyve-1 and some were integrated into the endothelium of the lymphatic vessels, revealing their plasticity in the nodular micro-environment. These results indicate that lymphatic as well as blood vascularization is induced around O. volvulus worms, either by the parasite itself, e.g. by the release of angiogenic and lymphangiogenic factors, or by consecutive host immune responses.

Roles of Prostaglandin E 2 –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

“…It was frequently reported that macrophages positive for LYVE-1 influence lymphangiogenesis. [41][42][43][44][45][46] In fact, we observed that the macrophage-like cells positive for LYVE-1 and VEGFR-3 accumulated to the granulation tissues. Furthermore, it was reported that VEGFR-1 tyrosine kinase signaling promotes lymphangiogenesis, as well as angiogenesis, indirectly via macrophage recruitment.…”

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

“…TAMs are critical regulators of angiogenesis and lymphangiogenesis; they express VEGFA and VEGFC and induce tip-cell formation and fusion (16,(30)(31)(32)(33). In addition, they are thought to directly contribute to lymphatic vessel formation by transdifferentiating into lymphatic endothelial cells (25,28,33,34).…”

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

“…It was observed that, at both sites, many of the nodules had become attached to host tissues and the majority of nodules had evidence of rapid host neovascularization. Vascularisation with both blood and lymphatic vessels is a consistent feature of O. volvulus nodule microarchitecture [50][51][52]. Whether neovascularisation is actively induced by pro-angiogenic parasite secretions [53] or is part of an innate inflammatory response to foreign material, remains to be resolved.…”

“…Because O. lienalis mf show a cumulative increase in recruitment to the skin during the first three weeks following inoculations in SCID mice [22] extended experiments are required to determine the dynamics of mf recruitment to the skin from implanted nodules. As lymphatic growth into nodular tissue has been proffered as an exit route for mf migration into the skin [52], this process may be dependent on lymphangiogenic responses developing within implanted nodules.…”