TRPML1 acts as a predisposing factor in lymphedema development by regulating the subcellular localization of...

An imbalance in lymphatic fluid, whether it is caused by generation, transport, outflow, or dysfunctional vessels, can lead to lymphedema; however, the exact pathogenesis of this disease remains unclear. To explore the mechanism, we focused on the association among TRPML1, aquaporin-3 (AQP3), and aquaporin-5 (AQP5) in human lymphatic endothelial cells (HLECs). We explored the role of TRPML1 in altering the permeability of HLECs in lymphedema. Meanwhile, we constructed a disease model using gene-knockout mice to observe the effect of TRPML1 on inflammation and fibrosis in lymphedema sites. Our results indicate that TRPML1 not only regulates the localization of AQP3, -5 to the cell membrane but also increases HLEC permeability, disrupts lymphatic fluid transport, and mediates the development of chronic inflammation at the site of lymphedema. Our study suggests that TRPML1 is a precipitating factor in lymphedema. Our findings improve the understanding of TRPML1 and aquaporins in secondary lymphedema, providing valuable insights for future research.