Sphingolipid Signaling Takes Center Stage in Regulation of Lymphatic–Immune Crosstalk in Lymphedema

he lymphatic vasculature maintains tissue homeostasis in several significant ways: (1) fluid control and solute balance, which prevents edema; (2) immune-cell activity regulation, which prevents autoimmunity and chronic inflammation; and (3) mediation of lipid transport, which notably prevents cholesterol buildup in the vascular wall.Consequently, dysregulated lymphatic transport contributes to various diseases such as obesity, irritable bowel syndrome, cardiovascular diseases (atherosclerosis, hypertension, heart failure), cancer metastasis, glaucoma, and neurodegenerative diseases.1,2 These discoveries have fueled significant progress in lymphatic biology since the first molecular characterization of lymphatic endothelial cells (LECs).3 In particular, lymphatic research is focused on elucidating the mechanisms that contribute to lymphedema, a debilitating chronic disease caused by lymphatic malfunction (eg, after parasitic infections) or induced by injury, radiation therapy, or lymphadenectomy in cancer patients.