Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Abstract

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.

Insights into IL-37, the role in autoimmune diseases

“…IL-37 overexpressing keratinocytes stimulated with M5 expressed lower levels of IL-6, IL-13, and psoriasin [15]. Keratin 14 VEGF-Atransgenic (K14-VEGF-tg) mouse model is a well-known psoriasis model, where VEGF is overexpressed in the epidermis, and the mouse spontaneously develops a chronic inflammatory skin disease with many features similar to human psoriasis [30]. K14-VEGF-tg mice injected with IL-37 displayed mild symptoms, such as scattered calluses, barely visible diabrosis, and scales, but histological analysis displayed psoriatic disease in mice treated with medium, characterized by epithelial parakeratosis and keratoplasia, severe lymphocyte infiltration into the dermis and epidermal layers, and apparent angiectasis.…”

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

“…Other studies using two models of acute cutaneous inflammation (one of oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation) in VEGF-C and VEGF-D transgenic mice reported that the delivery of VEGF-C-and VEGFR-3-specific ligand significantly limited acute skin inflammation. They concluded that the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage with no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu (Huggenberger et al 2010(Huggenberger et al , 2011Kajiya et al 2009). …”

Prominent Lymphatic Vessel Hyperplasia with Progressive Dysfunction and Distinct Immune Cell Infiltration in Lymphedema

“…13 Lymphatic vessels dynamically participate in inflammatory reactions, modulate immune responses and immune tolerance, and respond to increased fluid loads in the tissue. They expand in inflammation, and their activation reduces the severity of tissue inflammation, 14 highlighting an emerging role of the lymphatic vasculature as a therapeutic target. Inflammation also constitutes a hallmark of lymphedema in the clinic as well as in experimental models, 5,15 and it has been reported that cyclooxygenase 2 inhibitors reduce the severity of experimental secondary lymphedema, indicating a potential involvement of inflammation in lymphedema development.…”