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

Date Published: December 9, 2009

Publisher: Public Library of Science

Author(s): Tarik Attout, Achim Hoerauf, Gaëlle Dénécé, Alexander Yaw Debrah, Yeboah Marfo-Debrekyei, Michel Boussinesq, Samuel Wanji, Valérie Martinez, Sabine Mand, Ohene Adjei, Odile Bain, Sabine Specht, Coralie Martin, Derya Unutmaz.

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.

Partial Text: Onchocerciasis is caused by the filarial nematode Onchocerca volvulus. This disease is an important cause of visual impairment in African countries. Once the infective larvae penetrate into the skin during a blood meal of black fly vectors (Simulium spp.) they develop into male and female adult worms, residing in subcutaneous nodules (onchocercomas) and producing large numbers of microfilariae. In these nodules adult females can reach 70 cm in length. Although males can be observed alongside females within nodules, they are never identified alone in onchocercomas. This is also observed in cattle onchocercomas [1], [2] suggesting that nodules are induced by female filariae [3]. A particularity of onchocerciasis is the localisation of microfilariae in the dermis and not in the blood, unlike many other filarial species. Besides the skin, microfilariae are also able to migrate into the eye, where they can induce serious lesions.

This study provides evidences for the presence of lymphatic vessels and pro-vascular factors within the human Onchocerca nodule as well as of microfilariae within lymphatic capillary beds. It further suggests that CD68+ macrophages expressing the lymphatic endothelial marker Lyve-1 are recruited to the site of lymphangiogenesis and these cells may participate to the vessel formation in the nodule, as it has been shown in various pathologies [54].



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