Sodium-Directed Crosstalk Between Immune Cells and Lymphatic Vessels

The role of the lymphatic system in clearing extravasated fluids, lipid transport, and immune surveillance is well established, and lymphatic vasculature can provide a vital role in facilitating crosstalk among various organ systems. Lymphatic vessels rely on intrinsic and local factors to absorb and propel lymph from the interstitium back to the systemic circulation. The biological implications of local influences on lymphatic vessels are underscored by the exquisite sensitivity of these vessels to environmental stimuli. This review is intended to highlight the role of sodium within the local environment in mediating lymphatic and immune cell interactions that contribute to changes in function and disease progression.

We discuss evidence that accumulation of interstitial sodium modulates lymphatic growth, pumping dynamics, and permeability of renal lymphatics, which involves activation of sodium potassium chloride co-transporter (NKCC1) in lymphatic endothelial cells. These recent findings complement observations that sodium activates immune cells via the epithelial sodium channel (ENaC), leading to the formation and accumulation of lipid oxidation products, isolevuglandins (IsoLGs), in antigen presenting cells, which in turn promotes T cell activation and vasculopathy. In addition, we will underscore the physiologic relevance of altered interplay between immune cells and lymphatics in the sodium avid state that characterizes kidney diseases and consider how sodium accumulation in the interstitial compartment of the kidney modulates the lymphatic network and the interactions between renal lymphatics and activated immune cells. Finally, this article calls attention to persisting knowledge gaps and stresses the need for additional studies to identify salt-sensing mechanisms, including sodium-activated immune cells and lymphatic endothelial cell interactions, for targeted therapeutic interventions in the setting of renal disease.