Lymphotoxin-alpha contributes to lymphangiogenesis

Lymphotoxin-alpha (LT alpha), lymphotoxin-beta (LT beta), and tumor necrosis factor-alpha (TNF alpha) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LT alpha also contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LT alpha(-/-) mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LT alpha(-/-) mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type (WT) or LT alpha(-/-) mice, as did the skin draining immunization sites of LT beta(-/-) mice. Macrophages, B cells, and T cells, known sources of LT and TNF alpha, were apparent in the skin surrounding the immunization sites as were LT alpha, LT beta, and TNF alpha mRNAs. Ectopic expression of LT alpha led to the development of LYVE-1 and Prox1-positive lymphatic vessels within tertiary lymphoid organs (TLOs). Quantification of pancreatic lymphatic vessel density in RIPLT alpha LT beta(-/-) and WT mice revealed that LT alpha was sufficient for inducing lymphangiogenesis and that LT beta was not required for this process. Kidneys of inducible LT alpha transgenic mice developed lymphatic vessels before the appearance of obvious TLOs. These data indicate that LT alpha plays a significant role in lymphatic vessel function and in inflammation-associated lymphangiogenesis. (Blood. 2010;116(12):2173-2182)