Grant: Project Grant

Lymphatic vessels are part of the circulatory system. While blood vessels send nutrients and oxygen to the tissues, lymphatic vessels remove the extra interstitial fluid and tissue waste to maintain a healthy microenvironment. The central nervous system (CNS) has historically been viewed as an immune-privileged organ that lacks lymphatic vessels. It is thus puzzling how the brain maintains its fluid balance and removes toxic tissue waste. The recent discovery of the glymphatic system and meningeal lymphatic vessels solved this puzzle. This project aims to investigate how the brain lymphatic system is developed and maintained and potentially identify mechanisms that may regulate brain lymphatic function. During MLV development, MLV-associated macrophages undergo a substantial transition of populations. Our preliminary data showed that monocytes from the bone marrow migrated into the dura mater, differentiated into macrophages and replaced the neonatal macrophage populations. Interrupting monocyte-macrophage differentiation suppressed MLV development. Furthermore, depleting macrophages impaired both the structure and function of MLVs in adult mice. Compromised monocyte-macrophage differentiation also delayed the MLV recovery after the macrophage depletion, underscoring the importance of monocytes and macrophages in orchestrating brain lymphatic function. Based on preliminary studies, we hypothesize that monocytes and macrophages orchestrate brain lymphatic system, and alterations in these cells results in brain lymphatic dysfunction. We will test this hypothesis by investigating the role of monocytes and macrophages in regulating MLV development and their roles in maintaining MLVs in adult mice. Through this study, we anticipate understanding whether monocytes and macrophages may serve as novel therapeutic targets to improve brain lymphatic function in brain disorders.