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J Invest Dermatol. 2016 Mar;136(3):706-714. doi: 10.1016/j.jid.2015.12.001. Epub 2015 Dec 10.

Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema.

Author information

1
Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan; Department of Plastic and Reconstruction Surgery, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.
2
Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan; Translational Systems Biology and Medicine Initiative, Graduate School of Medicine, Hongo, Bunkyo, Tokyo, Japan.
3
Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.
4
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuo-ku, Kumamoto, Japan.
5
Department of Plastic and Reconstruction Surgery, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.
6
Section of Cellular Biochemistry, Department of Bio-matrix, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo, Tokyo, Japan.
7
Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan.
8
Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan; Department of Aging Research, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan. Electronic address: manabe-tky@umin.ac.jp.

Abstract

Lymphedema is a debilitating progressive condition that severely restricts quality of life and is frequently observed after cancer surgery. The mechanism underlying lymphedema development remains poorly understood, and no effective pharmacological means to prevent or alleviate the ailment is currently available. Using a mouse model of lymphedema, we show here that excessive generation of immature lymphatic vessels is essential for initial edema development and that this early process is also important for later development of lymphedema pathology. We found that CD4(+) T cells interact with macrophages to promote lymphangiogenesis, and that both lymphangiogenesis and edema were greatly reduced in macrophage-depleted mice, lymphocyte-deficient Rag2(?/?) mice or CD4(+) T-cell-deficient mice. Mechanistically, T helper type 1 and T helper type 17 cells activate lesional macrophages to produce vascular endothelial growth factor-C, which promotes lymphangiogenesis, and inhibition of this mechanism suppressed not only early lymphangiogenesis, but also later development of lymphedema. Finally, we show that atorvastatin suppresses excessive lymphangiogenesis and lymphedema by inhibiting T helper type 1 and T helper type 17 cell activation. These results demonstrate that the interaction between CD4(+) T cells and macrophages is a potential therapeutic target for prevention of lymphedema after surgery.

KEYWORDS:

LECs; T helper; Th; VEGF; VEGF receptor 3; VEGFR3; lymphatic endothelial cells; vascular endothelial growth factor

PMID:
27015456
DOI:
10.1016/j.jid.2015.12.001
[Indexed for MEDLINE]
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