Lymphoedema is a chronic debilitating disease caused by impaired lymphatic drainage and is characterized by tissue swelling, fat expansion, inflammation and fibrosis1,2. However, the exact mechanisms that drive lymphoedema are poorly understood. Although lymphatic vessels are known to transport cholesterol from peripheral tissues back to the systemic circulation3, the importance of impaired lymphatic drainage for cholesterol clearance in humans and its relevance to lymphoedema remain unknown. Here we show that lymphatic drainage insufficiency in human lymphoedema leads to excessive cholesterol accumulation in the lymphoedematous dermal tissue and around lymphatic vessels. Cholesterol deposition resulted in dermal adipose tissue remodelling, characterized by adipocyte hypertrophy and dysfunction, progressing to death and dermal fibrosis. Surgical intervention improved lymphatic drainage and reduced cholesterol deposition. Using two mouse models that reproduce features of human lymphoedema, we demonstrated that tissue swelling and dermal adipose tissue remodelling were ameliorated by the cholesterol-depleting agent cyclodextrin. Mechanistically, we demonstrated that cyclodextrin restored lymphatic drainage by promoting the regeneration of lymphatic vessels. This study unravels the role of impaired cholesterol clearance in driving lymphoedema and identifies tissue cholesterol as a promising therapeutic target for this currently incurable disease.
