(The) role of toll-like receptor 4 in lymphangiogenesis

Abstract

The lymphatic vessel is a major conduit for immune cell transport, however, little is known on how lymphatic vessels regulate immune cell trafficking and how lymphatic vessels themselves respond to inflammation. Toll-like receptor 4 (TLR4) plays a central role in lipopolysaccharide (LPS)-induced inflammation, but the role of TLR4 in lymphatic endothelial cells (LEC) is poorly understood. Here we found that LEC express high amounts of TLR4 in the intracellular region and that the TLR4 of LEC is the main mediator of nuclear factor-κB (NF-κB) activation by LPS. LPS-TLR4 signaling in LEC resulted in the production of various chemokines for chemotaxis of macrophage. Additionally, TLR4 in LEC actively contributed to the recruitment of macrophages to the draining lymphatic vessel. Furthermore, the macrophages that infiltrated into the lymphatic vessel induced lymphangiogenesis by secreting lymphangiogenic growth factors. These phenomena were largely attenuated not only in the mice defective in TLR4 signaling but also in the chimeric mice defective in TLR4 signaling that were recipients for bone marrow transplantation from normal TLR4 signaling mice. In conclusion, TLR4 in LEC plays an essential role in LPS-induced inflammatory lymphangiogenesis by chemotactic recruitment of macrophages.