Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation.

Huggenberger, Reto; Ullmann, Stefan; Proulx, Steven T; Pytowski, Bronislaw; Alitalo, Kari; Detmar, Michael (2010). Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. The Journal of experimental medicine, 207(10), pp. 2255-2269. Rockefeller Univ. Press 10.1084/jem.20100559

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The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Proulx, Steven Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1540-9538

Publisher:

Rockefeller Univ. Press

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

27 Oct 2020 11:58

Last Modified:

27 Oct 2020 13:49

Publisher DOI:

10.1084/jem.20100559

PubMed ID:

20837699

BORIS DOI:

10.7892/boris.147404

URI:

https://boris.unibe.ch/id/eprint/147404

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