Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes
- Monika Haemmerle1,
- Thomas Keller1,
- Gerda Egger1,
- Helga Schachner1,
- Carl Walter Steiner2,
- Dejan Stokic3,
- Christoph Neumayer4,
- Markus K. Brown1,
- Dontscho Kerjaschki1 and
- Brigitte Hantusch1⇑
- 1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
- 2Department of Internal Medicine, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
- 3Section for Science of Complex Systems, Medical University of Vienna, Vienna, Austria
- 4Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Corresponding author: Brigitte Hantusch, .
Type 2 diabetes is associated with microvascular damage that causes frequent infections in the skin and chronic ulcers as a result of impaired wound healing. To trace the pathological changes, we performed a comprehensive analysis of lymphatic vessels in the skin of type 2 diabetic versus nondiabetic patients. The dermis revealed enhanced lymphatic vessel density, and transcriptional profiling of ex vivo isolated lymphatic endothelial cells (LECs) identified 160 genes differentially expressed between type 2 diabetic and nondiabetic LECs. Bioinformatic analysis of deregulated genes uncovered sets functionally related to inflammation, lymphatic vessel remodeling, lymphangiogenesis, and lipid and small molecule transport. Furthermore, we traced CD68+ macrophage accumulation and concomitant upregulation of tumor necrosis factor-α (TNF-α) levels in type 2 diabetic skin. TNF-α treatment of LECs and its specific blockade in vitro reproduced differential regulation of a gene set that led to enhanced LEC mobility and macrophage attachment, which was mediated by the LEC-derived chemokine CXCL10. This study identifies lymph vessel gene signatures directly correlated with type 2 diabetes skin manifestations. In addition, we provide evidence for paracrine cross-talk fostering macrophage recruitment to LECs as one pathophysiological process that might contribute to aberrant lymphangiogenesis and persistent inflammation in the skin.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0844/-/DC1.
- Received June 22, 2012.
- Accepted February 9, 2013.
- © 2013 by the American Diabetes Association.
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