Swelling in the arms or legs might appear harmless at first. But for millions of people living with lymphoedema, the condition is chronic, progressive and often irreversible. Treatment options are also limited, and generally aim at managing swelling, but do not address the underlying causes.

Lymphoedema occurs when the lymphatic system breaks down. As the flow of lymph slows or stalls, fluid builds up in tissues, leading to chronic swelling of the limbs, inflammation and progressive tissue damage.

While it is well established that deposition of white adipose tissue (fat tissue) in the deeper layers of the skin is linked to disease progression, the importance of adipose tissue in the superficial layers of the skin near the surface, also called dermal adipose tissue (DAT), were largely overlooked.

This has changed with the publication of a study in Nature linking lymphoedema progression to phenotypical and functional changes of DAT. This work was conducted by researchers from the NUS Immunology Translational Research Programme (TRP).

Skin biopsies were obtained from patients with secondary lymphoedema, and changes in DAT across all stages were compared with healthy control tissues.

In normal skin, cholesterol is carried by high-density lipoprotein (HDL), along with fluids, through the lymphatic vessels to the blood circulation. Disruption of the lymphatic system causes fluid to accumulate and the peripheral tissue to swell. As a result, cholesterol accumulates in the tissue, leading to tissue remodelling. Adipocytes, or fat cells, become enlarged and clustered together. As the disease progresses, adipocytes undergo cell death, releasing cholesterol into the tissue spaces. As free cholesterol is toxic, macrophages are activated to clear it, and in the process, they transform into foam cells. This represents an inflammatory state which ultimately causes fibrosis.

To further investigate the mechanism, the team turned to clinical models that mimic key features of human lymphoedema. Since the accumulation of cholesterol drives lymphoedema progression, it was hypothesised that cholesterol clearance could ameliorate the disease.

When treated with cyclodextrin, a cyclic sugar molecule that removes cholesterol from tissues, swelling and tissue remodelling were significantly reduced. The treatment also stimulated the regeneration of lymphatic vessels, which restored lymphatic drainage. These data suggest that excess cholesterol in tissues is a major factor in the pathogenesis of lymphoedema, and that reducing tissue cholesterol may offer a potential therapeutic agent to treat lymphoedema.

Despite the strengths of the study, the team notes that the mechanism of how excess cholesterol disrupts the function of lymphatic vessels and the adipocytes remains unknown.

As there is no cure for secondary lymphoedema currently, and results from clinical trials with anti-inflammatory and anti-fibrotic agents have been discouraging. This study, however, provides a proof-of-principle that therapies aimed at cholesterol clearance may be effective in the treatment of lymphoedema.