Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes
Identifieur interne : 003668 ( Main/Exploration ); précédent : 003667; suivant : 003669Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes
Auteurs : Monika Haemmerle [Autriche] ; Thomas Keller [Autriche] ; Gerda Egger [Autriche] ; Helga Schachner [Autriche] ; Carl Walter Steiner [Autriche] ; Dejan Stokic [Autriche] ; Christoph Neumayer [Autriche] ; Markus K. Brown [Autriche] ; Dontscho Kerjaschki [Autriche] ; Brigitte Hantusch [Autriche]Source :
- Diabetes [ 0012-1797 ] ; 2013.
Abstract
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.
Url:
DOI: 10.2337/db12-0844
PubMed: 23423575
PubMed Central: 3712036
Affiliations:
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in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes</title><author><name sortKey="Haemmerle, Monika" sort="Haemmerle, Monika" uniqKey="Haemmerle M" first="Monika" last="Haemmerle">Monika Haemmerle</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Keller, Thomas" sort="Keller, Thomas" uniqKey="Keller T" first="Thomas" last="Keller">Thomas Keller</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Egger, Gerda" sort="Egger, Gerda" uniqKey="Egger G" first="Gerda" last="Egger">Gerda Egger</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Schachner, Helga" sort="Schachner, Helga" uniqKey="Schachner H" first="Helga" last="Schachner">Helga Schachner</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Steiner, Carl Walter" sort="Steiner, Carl Walter" uniqKey="Steiner C" first="Carl Walter" last="Steiner">Carl Walter Steiner</name><affiliation wicri:level="3"><nlm:aff id="aff2">Department of Internal Medicine, Division of Rheumatology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Department of Internal Medicine, Division of Rheumatology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Stokic, Dejan" sort="Stokic, Dejan" uniqKey="Stokic D" first="Dejan" last="Stokic">Dejan Stokic</name><affiliation wicri:level="3"><nlm:aff id="aff3">Section for Science of Complex Systems, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Section for Science of Complex Systems, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Neumayer, Christoph" sort="Neumayer, Christoph" uniqKey="Neumayer C" first="Christoph" last="Neumayer">Christoph Neumayer</name><affiliation wicri:level="3"><nlm:aff id="aff4">Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Brown, Markus K" sort="Brown, Markus K" uniqKey="Brown M" first="Markus K." last="Brown">Markus K. Brown</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Kerjaschki, Dontscho" sort="Kerjaschki, Dontscho" uniqKey="Kerjaschki D" first="Dontscho" last="Kerjaschki">Dontscho Kerjaschki</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author><author><name sortKey="Hantusch, Brigitte" sort="Hantusch, Brigitte" uniqKey="Hantusch B" first="Brigitte" last="Hantusch">Brigitte Hantusch</name><affiliation wicri:level="3"><nlm:aff id="aff1">Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Clinical Institute of Pathology, Medical University of Vienna, Vienna</wicri:regionArea><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation></author></analytic><series><title level="j">Diabetes</title><idno type="ISSN">0012-1797</idno><idno type="eISSN">1939-327X</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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<sup>+</sup> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Stumvoll, M" uniqKey="Stumvoll M">M Stumvoll</name></author><author><name sortKey="Goldstein, Bj" uniqKey="Goldstein B">BJ Goldstein</name></author><author><name sortKey="Van Haeften, Tw" uniqKey="Van Haeften T">TW van Haeften</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shoelson, Se" uniqKey="Shoelson S">SE Shoelson</name></author><author><name sortKey="Lee, J" uniqKey="Lee J">J Lee</name></author><author><name sortKey="Goldfine, Ab" uniqKey="Goldfine A">AB Goldfine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Ahilly, S" uniqKey="O Ahilly S">S 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uniqKey="Labanaris A">AP Labanaris</name></author><author><name sortKey="Polykandriotis, E" uniqKey="Polykandriotis E">E Polykandriotis</name></author><author><name sortKey="Horch, Re" uniqKey="Horch R">RE Horch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Von Der Weid, Py" uniqKey="Von Der Weid P">PY von der Weid</name></author><author><name sortKey="Rehal, S" uniqKey="Rehal S">S Rehal</name></author><author><name sortKey="Ferraz, Jg" uniqKey="Ferraz J">JG Ferraz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Ke" uniqKey="Kim K">KE Kim</name></author><author><name sortKey="Koh, Yj" uniqKey="Koh Y">YJ Koh</name></author><author><name sortKey="Jeon, Bh" uniqKey="Jeon B">BH Jeon</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Autriche</li></country><region><li>Vienne (Autriche)</li></region><settlement><li>Vienne (Autriche)</li></settlement></list><tree><country name="Autriche"><region name="Vienne (Autriche)"><name sortKey="Haemmerle, Monika" sort="Haemmerle, Monika" uniqKey="Haemmerle M" first="Monika" last="Haemmerle">Monika Haemmerle</name></region><name sortKey="Brown, Markus K" sort="Brown, Markus K" uniqKey="Brown M" first="Markus K." last="Brown">Markus K. Brown</name><name sortKey="Egger, Gerda" sort="Egger, Gerda" uniqKey="Egger G" first="Gerda" last="Egger">Gerda Egger</name><name sortKey="Hantusch, Brigitte" sort="Hantusch, Brigitte" uniqKey="Hantusch B" first="Brigitte" last="Hantusch">Brigitte Hantusch</name><name sortKey="Keller, Thomas" sort="Keller, Thomas" uniqKey="Keller T" first="Thomas" last="Keller">Thomas Keller</name><name sortKey="Kerjaschki, Dontscho" sort="Kerjaschki, Dontscho" uniqKey="Kerjaschki D" first="Dontscho" last="Kerjaschki">Dontscho Kerjaschki</name><name sortKey="Neumayer, Christoph" sort="Neumayer, Christoph" uniqKey="Neumayer C" first="Christoph" last="Neumayer">Christoph Neumayer</name><name sortKey="Schachner, Helga" sort="Schachner, Helga" uniqKey="Schachner H" first="Helga" last="Schachner">Helga Schachner</name><name sortKey="Steiner, Carl Walter" sort="Steiner, Carl Walter" uniqKey="Steiner C" first="Carl Walter" last="Steiner">Carl Walter Steiner</name><name sortKey="Stokic, Dejan" sort="Stokic, Dejan" uniqKey="Stokic D" first="Dejan" last="Stokic">Dejan Stokic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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