IL-6 regulates adipose deposition and homeostasis in lymphedema

Abstract

Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4+ cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4+ inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4+ cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.

Lymphatic Vessel Network Structure and Physiology

“…IL-6 is a known regulator of adipose homeostasis in obesity, and is elevated in primary and secondary models of lymphedema. Results in another study demonstrated the expression of IL-6 was associated with adipose deposition and CD4+ inflammation and was markedly decreased in CD4KO mice (224). In addition, loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury.…”

“…In addition, loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. The observations in these studies suggested that IL-6 is increased as a result of adipose deposition and CD4+ cell inflammation in lymphedema and that IL-6 expression in lymphedema acts to limit adipose accumulation (224). …”

Localized lymphedema after treatment for soft tissue sarcoma in the lower limbs: Comparison of improvement according to duration before lymphaticovenular anastomosis

“…LVA was performed 5 months after the onset of lymphedema in case 1, whereas more than 5 years had elapsed before LVA was performed in case 2. Accumulation of adipose and fibrous tissue tends to be progressive in patients in lymphedema, which contributes to the increasing size of the affected limb . Therefore, accumulation of adipose and fibrous tissue over a period of 5 years duration would have rendered volume reduction by LVA difficult in case 2.…”

“…Accumulation of adipose and fibrous tissue tends to be progressive in patients in lymphedema, which contributes to the increasing size of the affected limb. 11 Therefore, accumulation of adipose and fibrous tissue over a period of 5 years duration would have rendered volume reduction by LVA difficult in case 2. The difference in volume reduction between these two cases underscores the potential importance of performing LVA in the early stage of lymphedema.…”

Bridging the divide between pathogenesis and detection in lymphedema

“…Obesity has been linked with lymphedema risk, development and severity in numerous clinical trials and animal studies (6–21). While accumulation of adipose tissue is known to be a hallmark of the edematous limb and is seen in nearly all animal models of lymphedema (11, 12, 15, 18, 20), preoperative body-mass-index (BMI) is one of the few predisposing factors for lymphedema that has continuously been demonstrated in clinical trials (6, 13, 14, 16, 17, 19, 21). Utilizing this information coupled with other risk factors that can be easily measured such as elevated blood pressure (17) and the number of lymph nodes removed (6, 8, 22) could provide a powerful tool for identifying those patients most at risk.…”