In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. These results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation. (Blood. 2011;117(17):4667-4678) IntroductionAcute and chronic inflammatory processes are associated with the growth and/or enlargement of blood and lymphatic vessels. 1 Indeed, vascular remodeling is a hallmark of a plethora of inflammatory diseases, such as chronic airway inflammation, rheumatoid arthritis, inflammatory bowel disease, and the chronic inflammatory skin disease psoriasis. [2][3][4][5] We previously identified an important role of the blood vasculature and in particular of vascular endothelial growth factor (VEGF)-A in the promotion of acute and chronic inflammatory reactions in different experimental skin inflammation models. 6-11 Recently, we found that activation of VEGFR-3 had a potent anti-inflammatory effect in a mouse model of psoriasis. 12 Conversely, inhibition of VEGFR-3 significantly prolonged edema and inflammation during chronic bacterial airway inflammation, in chronic inflammatory arthritis, and in chronic skin inflammation. 3,12,13 However, it has also been reported that the lymphatic vasculature plays an active role in promoting corneal and kidney transplant rejections, in part by facilitating dendritic cell transport to draining lymph nodes. 14,15 Furthermore, the inflamed lymphatic endothelium might actively modulate immune responses. 16,17 Together, these results indicate an important role of blood vessel angiogenesis in sustaining inflammation, whereas the functional role of the lymphatic vasculature in acute inflammation has remained less explored.The cutaneous lymphatic vasculature is involved in the afferent immune response and also maintains tissue fluid homeostasis. [1...