Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema.
Identifieur interne : 001084 ( Main/Exploration ); précédent : 001083; suivant : 001085Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T Cells Drives the Pathogenesis of Lymphedema.
Auteurs : Fusa Ogata [Japon] ; Katsuhito Fujiu [Japon] ; Sahohime Matsumoto [Japon] ; Yukiteru Nakayama [Japon] ; Munehiko Shibata [Japon] ; Yuichi Oike [Japon] ; Isao Koshima [Japon] ; Tetsuro Watabe [Japon] ; Ryozo Nagai [Japon] ; Ichiro Manabe [Japon]Source :
- The Journal of investigative dermatology [ 1523-1747 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Cellules cultivées, Facteur de croissance endothéliale vasculaire de type A (métabolisme), Immunohistochimie, Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase (pharmacologie), Lymphangiogenèse (physiologie), Lymphocytes T CD4+ (), Lymphocytes T CD4+ (métabolisme), Lymphoedème (anatomopathologie), Lymphoedème (immunologie), Macrophages (cytologie), Macrophages (immunologie), Modèles animaux de maladie humaine, Ponction-biopsie à l'aiguille, Sensibilité et spécificité, Souris.
- MESH :
- anatomopathologie : Lymphoedème.
- cytologie : Macrophages.
- immunologie : Lymphoedème, Macrophages.
- métabolisme : Facteur de croissance endothéliale vasculaire de type A, Lymphocytes T CD4+.
- pharmacologie : Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase.
- physiologie : Lymphangiogenèse.
- Animaux, Cellules cultivées, Immunohistochimie, Lymphocytes T CD4+, Modèles animaux de maladie humaine, Ponction-biopsie à l'aiguille, Sensibilité et spécificité, Souris.
English descriptors
- KwdEn :
- Animals, Biopsy, Needle, CD4-Positive T-Lymphocytes (drug effects), CD4-Positive T-Lymphocytes (metabolism), Cells, Cultured, Disease Models, Animal, Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology), Immunohistochemistry, Lymphangiogenesis (physiology), Lymphedema (immunology), Lymphedema (pathology), Macrophages (cytology), Macrophages (immunology), Mice, Sensitivity and Specificity, Vascular Endothelial Growth Factor A (metabolism).
- MESH :
- chemical , metabolism : Vascular Endothelial Growth Factor A.
- chemical , pharmacology : Hydroxymethylglutaryl-CoA Reductase Inhibitors.
- cytology : Macrophages.
- drug effects : CD4-Positive T-Lymphocytes.
- immunology : Lymphedema, Macrophages.
- metabolism : CD4-Positive T-Lymphocytes.
- pathology : Lymphedema.
- physiology : Lymphangiogenesis.
- Animals, Biopsy, Needle, Cells, Cultured, Disease Models, Animal, Immunohistochemistry, Mice, Sensitivity and Specificity.
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.
DOI: 10.1016/j.jid.2015.12.001
PubMed: 27015456
Affiliations:
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University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>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</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Fujiu, Katsuhito" sort="Fujiu, Katsuhito" uniqKey="Fujiu K" first="Katsuhito" last="Fujiu">Katsuhito Fujiu</name><affiliation wicri:level="4"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>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</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Matsumoto, Sahohime" sort="Matsumoto, Sahohime" uniqKey="Matsumoto S" first="Sahohime" last="Matsumoto">Sahohime Matsumoto</name><affiliation wicri:level="4"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>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</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Nakayama, Yukiteru" sort="Nakayama, Yukiteru" uniqKey="Nakayama Y" first="Yukiteru" last="Nakayama">Yukiteru Nakayama</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Shibata, Munehiko" sort="Shibata, Munehiko" uniqKey="Shibata M" first="Munehiko" last="Shibata">Munehiko Shibata</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Cardiovascular Medicine, the University of Tokyo, Hongo, Bunkyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Oike, Yuichi" sort="Oike, Yuichi" uniqKey="Oike Y" first="Yuichi" last="Oike">Yuichi Oike</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuo-ku, Kumamoto, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuo-ku, Kumamoto</wicri:regionArea><wicri:noRegion>Kumamoto</wicri:noRegion></affiliation></author><author><name sortKey="Koshima, Isao" sort="Koshima, Isao" uniqKey="Koshima I" first="Isao" last="Koshima">Isao Koshima</name><affiliation wicri:level="4"><nlm:affiliation>Department of Plastic and Reconstruction Surgery, the University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Plastic and Reconstruction Surgery, the University of Tokyo, Hongo, Bunkyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Watabe, Tetsuro" sort="Watabe, Tetsuro" uniqKey="Watabe T" first="Tetsuro" last="Watabe">Tetsuro Watabe</name><affiliation wicri:level="3"><nlm:affiliation>Section of Cellular Biochemistry, Department of Bio-matrix, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Section of Cellular Biochemistry, Department of Bio-matrix, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Nagai, Ryozo" sort="Nagai, Ryozo" uniqKey="Nagai R" first="Ryozo" last="Nagai">Ryozo Nagai</name><affiliation wicri:level="1"><nlm:affiliation>Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi</wicri:regionArea><wicri:noRegion>Tochigi</wicri:noRegion></affiliation></author><author><name sortKey="Manabe, Ichiro" sort="Manabe, Ichiro" uniqKey="Manabe I" first="Ichiro" last="Manabe">Ichiro Manabe</name><affiliation wicri:level="4"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>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</wicri:regionArea><orgName type="university">Université de Tokyo</orgName><placeName><settlement type="city">Tokyo</settlement><region type="province">Région de Kantō</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of investigative dermatology</title><idno type="eISSN">1523-1747</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Biopsy, Needle</term><term>CD4-Positive T-Lymphocytes (drug effects)</term><term>CD4-Positive T-Lymphocytes (metabolism)</term><term>Cells, Cultured</term><term>Disease Models, Animal</term><term>Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)</term><term>Immunohistochemistry</term><term>Lymphangiogenesis (physiology)</term><term>Lymphedema (immunology)</term><term>Lymphedema (pathology)</term><term>Macrophages (cytology)</term><term>Macrophages (immunology)</term><term>Mice</term><term>Sensitivity and Specificity</term><term>Vascular Endothelial Growth Factor A (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules cultivées</term><term>Facteur de croissance endothéliale vasculaire de type A (métabolisme)</term><term>Immunohistochimie</term><term>Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase (pharmacologie)</term><term>Lymphangiogenèse (physiologie)</term><term>Lymphocytes T CD4+ ()</term><term>Lymphocytes T CD4+ (métabolisme)</term><term>Lymphoedème (anatomopathologie)</term><term>Lymphoedème (immunologie)</term><term>Macrophages (cytologie)</term><term>Macrophages (immunologie)</term><term>Modèles animaux de maladie humaine</term><term>Ponction-biopsie à l'aiguille</term><term>Sensibilité et spécificité</term><term>Souris</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Vascular Endothelial Growth Factor A</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Hydroxymethylglutaryl-CoA Reductase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Lymphoedème</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>CD4-Positive T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Lymphoedème</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Lymphedema</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>CD4-Positive T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur de croissance endothéliale vasculaire de type A</term><term>Lymphocytes T CD4+</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lymphedema</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Lymphangiogenèse</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Lymphangiogenesis</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Biopsy, Needle</term><term>Cells, Cultured</term><term>Disease Models, Animal</term><term>Immunohistochemistry</term><term>Mice</term><term>Sensitivity and Specificity</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules cultivées</term><term>Immunohistochimie</term><term>Lymphocytes T CD4+</term><term>Modèles animaux de maladie humaine</term><term>Ponction-biopsie à l'aiguille</term><term>Sensibilité et spécificité</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement><orgName><li>Université de Tokyo</li></orgName></list><tree><country name="Japon"><region name="Région de Kantō"><name sortKey="Ogata, Fusa" sort="Ogata, Fusa" uniqKey="Ogata F" first="Fusa" last="Ogata">Fusa Ogata</name></region><name sortKey="Fujiu, Katsuhito" sort="Fujiu, Katsuhito" uniqKey="Fujiu K" first="Katsuhito" last="Fujiu">Katsuhito Fujiu</name><name sortKey="Koshima, Isao" sort="Koshima, Isao" uniqKey="Koshima I" first="Isao" last="Koshima">Isao Koshima</name><name sortKey="Manabe, Ichiro" sort="Manabe, Ichiro" uniqKey="Manabe I" first="Ichiro" last="Manabe">Ichiro Manabe</name><name sortKey="Matsumoto, Sahohime" sort="Matsumoto, Sahohime" uniqKey="Matsumoto S" first="Sahohime" last="Matsumoto">Sahohime Matsumoto</name><name sortKey="Nagai, Ryozo" sort="Nagai, Ryozo" uniqKey="Nagai R" first="Ryozo" last="Nagai">Ryozo Nagai</name><name sortKey="Nakayama, Yukiteru" sort="Nakayama, Yukiteru" uniqKey="Nakayama Y" first="Yukiteru" last="Nakayama">Yukiteru Nakayama</name><name sortKey="Oike, Yuichi" sort="Oike, Yuichi" uniqKey="Oike Y" first="Yuichi" last="Oike">Yuichi Oike</name><name sortKey="Shibata, Munehiko" sort="Shibata, Munehiko" uniqKey="Shibata M" first="Munehiko" last="Shibata">Munehiko Shibata</name><name sortKey="Watabe, Tetsuro" sort="Watabe, Tetsuro" uniqKey="Watabe T" first="Tetsuro" last="Watabe">Tetsuro Watabe</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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