LymphedemaV1, Ncbi, Merge, bibRecord, 004791

Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury

Identifieur interne : 004791 ( Ncbi/Merge ); précédent : 004790; suivant : 004792

Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury

Auteurs : Jamie C. Zampell ; Sonia Elhadad ; Tomer Avraham ; Evan Weitman ; Seth Aschen ; Alan Yan ; Babak J. Mehrara

Source :

American Journal of Physiology - Cell Physiology [ 0363-6143 ] ; 2011.

RBID : PMC:3287358

Descripteurs français

English descriptors

KwdEn :
- Animals, Collagen (immunology), Collagen (metabolism), Female, Fibrosis (complications), Fibrosis (immunology), Fibrosis (metabolism), Fibrosis (pathology), Gene Deletion, Gene Expression (immunology), Glycoproteins (immunology), Glycoproteins (metabolism), Immunity, Innate, Inflammation (complications), Inflammation (immunology), Inflammation (metabolism), Inflammation (pathology), Leukemic Infiltration (complications), Leukemic Infiltration (metabolism), Leukemic Infiltration (pathology), Lymphangiogenesis (genetics), Lymphangiogenesis (immunology), Lymphatic Vessels (immunology), Lymphatic Vessels (injuries), Lymphatic Vessels (metabolism), Lymphedema (complications), Lymphedema (immunology), Lymphedema (metabolism), Lymphedema (pathology), Macrophages (cytology), Macrophages (immunology), Macrophages (metabolism), Mice, Mice, Knockout, Signal Transduction (immunology), Toll-Like Receptor 2 (deficiency), Toll-Like Receptor 2 (genetics), Toll-Like Receptor 4 (deficiency), Toll-Like Receptor 4 (genetics), Toll-Like Receptor 9 (deficiency), Toll-Like Receptor 9 (genetics), Transforming Growth Factor beta1 (immunology), Transforming Growth Factor beta1 (metabolism), Vascular Endothelial Growth Factor C (immunology), Vascular Endothelial Growth Factor C (metabolism).
MESH :
- chemical , deficiency : Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptor 9.
- chemical , genetics : Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptor 9.
- chemical , immunology : Collagen, Glycoproteins, Transforming Growth Factor beta1, Vascular Endothelial Growth Factor C.
- chemical , metabolism : Collagen, Glycoproteins, Transforming Growth Factor beta1, Vascular Endothelial Growth Factor C.
- complications : Fibrosis, Inflammation, Leukemic Infiltration, Lymphedema.
- cytology : Macrophages.
- genetics : Lymphangiogenesis.
- immunology : Fibrosis, Gene Expression, Inflammation, Lymphangiogenesis, Lymphatic Vessels, Lymphedema, Macrophages, Signal Transduction.
- injuries : Lymphatic Vessels.
- metabolism : Fibrosis, Inflammation, Leukemic Infiltration, Lymphatic Vessels, Lymphedema, Macrophages.
- pathology : Fibrosis, Inflammation, Leukemic Infiltration, Lymphedema.
- Animals, Female, Gene Deletion, Immunity, Innate, Mice, Mice, Knockout.

Abstract

Mechanisms regulating lymphedema pathogenesis remain unknown. Recently, we have shown that lymphatic fluid stasis increases endogenous danger signal expression, and these molecules influence lymphatic repair (Zampbell JC, et al. Am J Physiol Cell Physiol 300: C1107–C1121, 2011). Endogenous danger signals activate Toll-like receptors (TLR) 2, 4, and 9 and induce homeostatic or harmful responses, depending on physiological context. The purpose of this study was to determine the role of TLRs in regulating tissue responses to lymphatic fluid stasis. A surgical model of lymphedema was used in which wild-type or TLR2, 4, or 9 knockout (KO) mice underwent tail lymphatic excision. Six weeks postoperatively, TLR KOs demonstrated markedly increased tail edema compared with wild-type animals (50–200% increase; P < 0.01), and this effect was most pronounced in TLR4 KOs (P < 0.01). TLR deficiency resulted in decreased interstitial and lymphatic transport, abnormal lymphatic architecture, and fewer capillary lymphatics (40–50% decrease; P < 0.001). Lymphedematous tissues of TLR KOs demonstrated increased leukocyte infiltration (P < 0.001 for TLR4 KOs), including higher numbers of infiltrating CD3+ cells (P < 0.05, TLR4 and TLR9 KO), yet decreased infiltrating F4/80+ macrophages (P < 0.05, all groups). Furthermore, analysis of isolated macrophages revealed twofold reductions in VEGF-C (P < 0.01) and LYVE-1 (P < 0.05) mRNA from TLR2-deficient animals. Finally, TLR deficiency was associated with increased collagen type I deposition and increased transforming growth factor-β1 expression (P < 0.01, TLR4 and TLR9 KO), contributing to dermal fibrosis. In conclusion, TLR deficiency worsens tissue responses to lymphatic fluid stasis and is associated with decreased lymphangiogenesis, increased fibrosis, and reduced macrophage infiltration. These findings suggest a role for innate immune responses, including TLR signaling, in lymphatic repair and lymphedema pathogenesis.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287358

DOI: 10.1152/ajpcell.00284.2011
PubMed: 22049214
PubMed Central: 3287358

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Le document en format XML

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<term>Collagen (immunology)</term>
<term>Collagen (metabolism)</term>
<term>Female</term>
<term>Fibrosis (complications)</term>
<term>Fibrosis (immunology)</term>
<term>Fibrosis (metabolism)</term>
<term>Fibrosis (pathology)</term>
<term>Gene Deletion</term>
<term>Gene Expression (immunology)</term>
<term>Glycoproteins (immunology)</term>
<term>Glycoproteins (metabolism)</term>
<term>Immunity, Innate</term>
<term>Inflammation (complications)</term>
<term>Inflammation (immunology)</term>
<term>Inflammation (metabolism)</term>
<term>Inflammation (pathology)</term>
<term>Leukemic Infiltration (complications)</term>
<term>Leukemic Infiltration (metabolism)</term>
<term>Leukemic Infiltration (pathology)</term>
<term>Lymphangiogenesis (genetics)</term>
<term>Lymphangiogenesis (immunology)</term>
<term>Lymphatic Vessels (immunology)</term>
<term>Lymphatic Vessels (injuries)</term>
<term>Lymphatic Vessels (metabolism)</term>
<term>Lymphedema (complications)</term>
<term>Lymphedema (immunology)</term>
<term>Lymphedema (metabolism)</term>
<term>Lymphedema (pathology)</term>
<term>Macrophages (cytology)</term>
<term>Macrophages (immunology)</term>
<term>Macrophages (metabolism)</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Signal Transduction (immunology)</term>
<term>Toll-Like Receptor 2 (deficiency)</term>
<term>Toll-Like Receptor 2 (genetics)</term>
<term>Toll-Like Receptor 4 (deficiency)</term>
<term>Toll-Like Receptor 4 (genetics)</term>
<term>Toll-Like Receptor 9 (deficiency)</term>
<term>Toll-Like Receptor 9 (genetics)</term>
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<term>Vascular Endothelial Growth Factor C (metabolism)</term>
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<term>Collagène (immunologie)</term>
<term>Collagène (métabolisme)</term>
<term>Délétion de gène</term>
<term>Expression des gènes (immunologie)</term>
<term>Facteur de croissance endothéliale vasculaire de type C (immunologie)</term>
<term>Facteur de croissance endothéliale vasculaire de type C (métabolisme)</term>
<term>Facteur de croissance transformant bêta-1 (immunologie)</term>
<term>Facteur de croissance transformant bêta-1 (métabolisme)</term>
<term>Femelle</term>
<term>Fibrose ()</term>
<term>Fibrose (anatomopathologie)</term>
<term>Fibrose (immunologie)</term>
<term>Fibrose (métabolisme)</term>
<term>Glycoprotéines (immunologie)</term>
<term>Glycoprotéines (métabolisme)</term>
<term>Immunité innée</term>
<term>Infiltration leucémique ()</term>
<term>Infiltration leucémique (anatomopathologie)</term>
<term>Infiltration leucémique (métabolisme)</term>
<term>Inflammation ()</term>
<term>Inflammation (anatomopathologie)</term>
<term>Inflammation (immunologie)</term>
<term>Inflammation (métabolisme)</term>
<term>Lymphangiogenèse (génétique)</term>
<term>Lymphangiogenèse (immunologie)</term>
<term>Lymphoedème ()</term>
<term>Lymphoedème (anatomopathologie)</term>
<term>Lymphoedème (immunologie)</term>
<term>Lymphoedème (métabolisme)</term>
<term>Macrophages (cytologie)</term>
<term>Macrophages (immunologie)</term>
<term>Macrophages (métabolisme)</term>
<term>Récepteur de type Toll-2 (déficit)</term>
<term>Récepteur de type Toll-2 (génétique)</term>
<term>Récepteur de type Toll-4 (déficit)</term>
<term>Récepteur de type Toll-4 (génétique)</term>
<term>Récepteur-9 de type Toll-like (déficit)</term>
<term>Récepteur-9 de type Toll-like (génétique)</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Transduction du signal (immunologie)</term>
<term>Vaisseaux lymphatiques (immunologie)</term>
<term>Vaisseaux lymphatiques (métabolisme)</term>
<term>Vaisseaux lymphatiques (traumatismes)</term>
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<term>Toll-Like Receptor 9</term>
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<term>Glycoproteins</term>
<term>Transforming Growth Factor beta1</term>
<term>Vascular Endothelial Growth Factor C</term>
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<term>Glycoproteins</term>
<term>Transforming Growth Factor beta1</term>
<term>Vascular Endothelial Growth Factor C</term>
</keywords>
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<term>Infiltration leucémique</term>
<term>Inflammation</term>
<term>Lymphoedème</term>
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<term>Récepteur de type Toll-4</term>
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<term>Glycoprotéines</term>
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<term>Macrophages</term>
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<term>Lymphedema</term>
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<term>Signal Transduction</term>
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<term>Glycoprotéines</term>
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<term>Inflammation</term>
<term>Lymphoedème</term>
<term>Macrophages</term>
<term>Vaisseaux lymphatiques</term>
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<term>Inflammation</term>
<term>Leukemic Infiltration</term>
<term>Lymphedema</term>
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<front><div type="abstract" xml:lang="en"><p>Mechanisms regulating lymphedema pathogenesis remain unknown. Recently, we have shown that lymphatic fluid stasis increases endogenous danger signal expression, and these molecules influence lymphatic repair (Zampbell JC, et al. <italic>Am J Physiol Cell Physiol</italic>
 300: C1107–C1121, 2011). Endogenous danger signals activate Toll-like receptors (TLR) 2, 4, and 9 and induce homeostatic or harmful responses, depending on physiological context. The purpose of this study was to determine the role of TLRs in regulating tissue responses to lymphatic fluid stasis. A surgical model of lymphedema was used in which wild-type or TLR2, 4, or 9 knockout (KO) mice underwent tail lymphatic excision. Six weeks postoperatively, TLR KOs demonstrated markedly increased tail edema compared with wild-type animals (50–200% increase; <italic>P</italic>
 < 0.01), and this effect was most pronounced in TLR4 KOs (<italic>P</italic>
 < 0.01). TLR deficiency resulted in decreased interstitial and lymphatic transport, abnormal lymphatic architecture, and fewer capillary lymphatics (40–50% decrease; <italic>P</italic>
 < 0.001). Lymphedematous tissues of TLR KOs demonstrated increased leukocyte infiltration (<italic>P</italic>
 < 0.001 for TLR4 KOs), including higher numbers of infiltrating CD3+ cells (<italic>P</italic>
 < 0.05, TLR4 and TLR9 KO), yet decreased infiltrating F4/80+ macrophages (<italic>P</italic>
 < 0.05, all groups). Furthermore, analysis of isolated macrophages revealed twofold reductions in VEGF-C (<italic>P</italic>
 < 0.01) and LYVE-1 (<italic>P</italic>
 < 0.05) mRNA from TLR2-deficient animals. Finally, TLR deficiency was associated with increased collagen type I deposition and increased transforming growth factor-β1 expression (<italic>P</italic>
 < 0.01, TLR4 and TLR9 KO), contributing to dermal fibrosis. In conclusion, TLR deficiency worsens tissue responses to lymphatic fluid stasis and is associated with decreased lymphangiogenesis, increased fibrosis, and reduced macrophage infiltration. These findings suggest a role for innate immune responses, including TLR signaling, in lymphatic repair and lymphedema pathogenesis.</p>
</div>
</front>
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<front><div type="abstract" xml:lang="en"><p>Mechanisms regulating lymphedema pathogenesis remain unknown. Recently, we have shown that lymphatic fluid stasis increases endogenous danger signal expression, and these molecules influence lymphatic repair (Zampbell JC, et al. <italic>Am J Physiol Cell Physiol</italic>
 300: C1107–C1121, 2011). Endogenous danger signals activate Toll-like receptors (TLR) 2, 4, and 9 and induce homeostatic or harmful responses, depending on physiological context. The purpose of this study was to determine the role of TLRs in regulating tissue responses to lymphatic fluid stasis. A surgical model of lymphedema was used in which wild-type or TLR2, 4, or 9 knockout (KO) mice underwent tail lymphatic excision. Six weeks postoperatively, TLR KOs demonstrated markedly increased tail edema compared with wild-type animals (50–200% increase; <italic>P</italic>
 < 0.01), and this effect was most pronounced in TLR4 KOs (<italic>P</italic>
 < 0.01). TLR deficiency resulted in decreased interstitial and lymphatic transport, abnormal lymphatic architecture, and fewer capillary lymphatics (40–50% decrease; <italic>P</italic>
 < 0.001). Lymphedematous tissues of TLR KOs demonstrated increased leukocyte infiltration (<italic>P</italic>
 < 0.001 for TLR4 KOs), including higher numbers of infiltrating CD3+ cells (<italic>P</italic>
 < 0.05, TLR4 and TLR9 KO), yet decreased infiltrating F4/80+ macrophages (<italic>P</italic>
 < 0.05, all groups). Furthermore, analysis of isolated macrophages revealed twofold reductions in VEGF-C (<italic>P</italic>
 < 0.01) and LYVE-1 (<italic>P</italic>
 < 0.05) mRNA from TLR2-deficient animals. Finally, TLR deficiency was associated with increased collagen type I deposition and increased transforming growth factor-β1 expression (<italic>P</italic>
 < 0.01, TLR4 and TLR9 KO), contributing to dermal fibrosis. In conclusion, TLR deficiency worsens tissue responses to lymphatic fluid stasis and is associated with decreased lymphangiogenesis, increased fibrosis, and reduced macrophage infiltration. These findings suggest a role for innate immune responses, including TLR signaling, in lymphatic repair and lymphedema pathogenesis.</p>
</div>
</front>
</TEI>
</pmc>
<pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury.</title>
<author><name sortKey="Zampell, Jamie C" sort="Zampell, Jamie C" uniqKey="Zampell J" first="Jamie C" last="Zampell">Jamie C. Zampell</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Elhadad, Sonia" sort="Elhadad, Sonia" uniqKey="Elhadad S" first="Sonia" last="Elhadad">Sonia Elhadad</name>
</author>
<author><name sortKey="Avraham, Tomer" sort="Avraham, Tomer" uniqKey="Avraham T" first="Tomer" last="Avraham">Tomer Avraham</name>
</author>
<author><name sortKey="Weitman, Evan" sort="Weitman, Evan" uniqKey="Weitman E" first="Evan" last="Weitman">Evan Weitman</name>
</author>
<author><name sortKey="Aschen, Seth" sort="Aschen, Seth" uniqKey="Aschen S" first="Seth" last="Aschen">Seth Aschen</name>
</author>
<author><name sortKey="Yan, Alan" sort="Yan, Alan" uniqKey="Yan A" first="Alan" last="Yan">Alan Yan</name>
</author>
<author><name sortKey="Mehrara, Babak J" sort="Mehrara, Babak J" uniqKey="Mehrara B" first="Babak J" last="Mehrara">Babak J. Mehrara</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2012">2012</date>
<idno type="RBID">pubmed:22049214</idno>
<idno type="pmid">22049214</idno>
<idno type="doi">10.1152/ajpcell.00284.2011</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury.</title>
<author><name sortKey="Zampell, Jamie C" sort="Zampell, Jamie C" uniqKey="Zampell J" first="Jamie C" last="Zampell">Jamie C. Zampell</name>
<affiliation wicri:level="2"><nlm:affiliation>Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Elhadad, Sonia" sort="Elhadad, Sonia" uniqKey="Elhadad S" first="Sonia" last="Elhadad">Sonia Elhadad</name>
</author>
<author><name sortKey="Avraham, Tomer" sort="Avraham, Tomer" uniqKey="Avraham T" first="Tomer" last="Avraham">Tomer Avraham</name>
</author>
<author><name sortKey="Weitman, Evan" sort="Weitman, Evan" uniqKey="Weitman E" first="Evan" last="Weitman">Evan Weitman</name>
</author>
<author><name sortKey="Aschen, Seth" sort="Aschen, Seth" uniqKey="Aschen S" first="Seth" last="Aschen">Seth Aschen</name>
</author>
<author><name sortKey="Yan, Alan" sort="Yan, Alan" uniqKey="Yan A" first="Alan" last="Yan">Alan Yan</name>
</author>
<author><name sortKey="Mehrara, Babak J" sort="Mehrara, Babak J" uniqKey="Mehrara B" first="Babak J" last="Mehrara">Babak J. Mehrara</name>
</author>
</analytic>
<series><title level="j">American journal of physiology. Cell physiology</title>
<idno type="eISSN">1522-1563</idno>
<imprint><date when="2012" type="published">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Collagen (immunology)</term>
<term>Collagen (metabolism)</term>
<term>Female</term>
<term>Fibrosis (complications)</term>
<term>Fibrosis (immunology)</term>
<term>Fibrosis (metabolism)</term>
<term>Fibrosis (pathology)</term>
<term>Gene Deletion</term>
<term>Gene Expression (immunology)</term>
<term>Glycoproteins (immunology)</term>
<term>Glycoproteins (metabolism)</term>
<term>Immunity, Innate</term>
<term>Inflammation (complications)</term>
<term>Inflammation (immunology)</term>
<term>Inflammation (metabolism)</term>
<term>Inflammation (pathology)</term>
<term>Leukemic Infiltration (complications)</term>
<term>Leukemic Infiltration (metabolism)</term>
<term>Leukemic Infiltration (pathology)</term>
<term>Lymphangiogenesis (genetics)</term>
<term>Lymphangiogenesis (immunology)</term>
<term>Lymphatic Vessels (immunology)</term>
<term>Lymphatic Vessels (injuries)</term>
<term>Lymphatic Vessels (metabolism)</term>
<term>Lymphedema (complications)</term>
<term>Lymphedema (immunology)</term>
<term>Lymphedema (metabolism)</term>
<term>Lymphedema (pathology)</term>
<term>Macrophages (cytology)</term>
<term>Macrophages (immunology)</term>
<term>Macrophages (metabolism)</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Signal Transduction (immunology)</term>
<term>Toll-Like Receptor 2 (deficiency)</term>
<term>Toll-Like Receptor 2 (genetics)</term>
<term>Toll-Like Receptor 4 (deficiency)</term>
<term>Toll-Like Receptor 4 (genetics)</term>
<term>Toll-Like Receptor 9 (deficiency)</term>
<term>Toll-Like Receptor 9 (genetics)</term>
<term>Transforming Growth Factor beta1 (immunology)</term>
<term>Transforming Growth Factor beta1 (metabolism)</term>
<term>Vascular Endothelial Growth Factor C (immunology)</term>
<term>Vascular Endothelial Growth Factor C (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Collagène (immunologie)</term>
<term>Collagène (métabolisme)</term>
<term>Délétion de gène</term>
<term>Expression des gènes (immunologie)</term>
<term>Facteur de croissance endothéliale vasculaire de type C (immunologie)</term>
<term>Facteur de croissance endothéliale vasculaire de type C (métabolisme)</term>
<term>Facteur de croissance transformant bêta-1 (immunologie)</term>
<term>Facteur de croissance transformant bêta-1 (métabolisme)</term>
<term>Femelle</term>
<term>Fibrose ()</term>
<term>Fibrose (anatomopathologie)</term>
<term>Fibrose (immunologie)</term>
<term>Fibrose (métabolisme)</term>
<term>Glycoprotéines (immunologie)</term>
<term>Glycoprotéines (métabolisme)</term>
<term>Immunité innée</term>
<term>Infiltration leucémique ()</term>
<term>Infiltration leucémique (anatomopathologie)</term>
<term>Infiltration leucémique (métabolisme)</term>
<term>Inflammation ()</term>
<term>Inflammation (anatomopathologie)</term>
<term>Inflammation (immunologie)</term>
<term>Inflammation (métabolisme)</term>
<term>Lymphangiogenèse (génétique)</term>
<term>Lymphangiogenèse (immunologie)</term>
<term>Lymphoedème ()</term>
<term>Lymphoedème (anatomopathologie)</term>
<term>Lymphoedème (immunologie)</term>
<term>Lymphoedème (métabolisme)</term>
<term>Macrophages (cytologie)</term>
<term>Macrophages (immunologie)</term>
<term>Macrophages (métabolisme)</term>
<term>Récepteur de type Toll-2 (déficit)</term>
<term>Récepteur de type Toll-2 (génétique)</term>
<term>Récepteur de type Toll-4 (déficit)</term>
<term>Récepteur de type Toll-4 (génétique)</term>
<term>Récepteur-9 de type Toll-like (déficit)</term>
<term>Récepteur-9 de type Toll-like (génétique)</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Transduction du signal (immunologie)</term>
<term>Vaisseaux lymphatiques (immunologie)</term>
<term>Vaisseaux lymphatiques (métabolisme)</term>
<term>Vaisseaux lymphatiques (traumatismes)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Toll-Like Receptor 2</term>
<term>Toll-Like Receptor 4</term>
<term>Toll-Like Receptor 9</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Toll-Like Receptor 2</term>
<term>Toll-Like Receptor 4</term>
<term>Toll-Like Receptor 9</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Collagen</term>
<term>Glycoproteins</term>
<term>Transforming Growth Factor beta1</term>
<term>Vascular Endothelial Growth Factor C</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Collagen</term>
<term>Glycoproteins</term>
<term>Transforming Growth Factor beta1</term>
<term>Vascular Endothelial Growth Factor C</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Fibrose</term>
<term>Infiltration leucémique</term>
<term>Inflammation</term>
<term>Lymphoedème</term>
</keywords>
<keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Fibrosis</term>
<term>Inflammation</term>
<term>Leukemic Infiltration</term>
<term>Lymphedema</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="déficit" xml:lang="fr"><term>Récepteur de type Toll-2</term>
<term>Récepteur de type Toll-4</term>
<term>Récepteur-9 de type Toll-like</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lymphangiogenesis</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Lymphangiogenèse</term>
<term>Récepteur de type Toll-2</term>
<term>Récepteur de type Toll-4</term>
<term>Récepteur-9 de type Toll-like</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Collagène</term>
<term>Expression des gènes</term>
<term>Facteur de croissance endothéliale vasculaire de type C</term>
<term>Facteur de croissance transformant bêta-1</term>
<term>Fibrose</term>
<term>Glycoprotéines</term>
<term>Inflammation</term>
<term>Lymphangiogenèse</term>
<term>Lymphoedème</term>
<term>Macrophages</term>
<term>Transduction du signal</term>
<term>Vaisseaux lymphatiques</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Fibrosis</term>
<term>Gene Expression</term>
<term>Inflammation</term>
<term>Lymphangiogenesis</term>
<term>Lymphatic Vessels</term>
<term>Lymphedema</term>
<term>Macrophages</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="injuries" xml:lang="en"><term>Lymphatic Vessels</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Fibrosis</term>
<term>Inflammation</term>
<term>Leukemic Infiltration</term>
<term>Lymphatic Vessels</term>
<term>Lymphedema</term>
<term>Macrophages</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Collagène</term>
<term>Facteur de croissance endothéliale vasculaire de type C</term>
<term>Facteur de croissance transformant bêta-1</term>
<term>Fibrose</term>
<term>Glycoprotéines</term>
<term>Infiltration leucémique</term>
<term>Inflammation</term>
<term>Lymphoedème</term>
<term>Macrophages</term>
<term>Vaisseaux lymphatiques</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Fibrosis</term>
<term>Inflammation</term>
<term>Leukemic Infiltration</term>
<term>Lymphedema</term>
</keywords>
<keywords scheme="MESH" qualifier="traumatismes" xml:lang="fr"><term>Vaisseaux lymphatiques</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Female</term>
<term>Gene Deletion</term>
<term>Immunity, Innate</term>
<term>Mice</term>
<term>Mice, Knockout</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Délétion de gène</term>
<term>Femelle</term>
<term>Fibrose</term>
<term>Immunité innée</term>
<term>Infiltration leucémique</term>
<term>Inflammation</term>
<term>Lymphoedème</term>
<term>Souris</term>
<term>Souris knockout</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Mechanisms regulating lymphedema pathogenesis remain unknown. Recently, we have shown that lymphatic fluid stasis increases endogenous danger signal expression, and these molecules influence lymphatic repair (Zampbell JC, et al. Am J Physiol Cell Physiol 300: C1107-C1121, 2011). Endogenous danger signals activate Toll-like receptors (TLR) 2, 4, and 9 and induce homeostatic or harmful responses, depending on physiological context. The purpose of this study was to determine the role of TLRs in regulating tissue responses to lymphatic fluid stasis. A surgical model of lymphedema was used in which wild-type or TLR2, 4, or 9 knockout (KO) mice underwent tail lymphatic excision. Six weeks postoperatively, TLR KOs demonstrated markedly increased tail edema compared with wild-type animals (50-200% increase; P < 0.01), and this effect was most pronounced in TLR4 KOs (P < 0.01). TLR deficiency resulted in decreased interstitial and lymphatic transport, abnormal lymphatic architecture, and fewer capillary lymphatics (40-50% decrease; P < 0.001). Lymphedematous tissues of TLR KOs demonstrated increased leukocyte infiltration (P < 0.001 for TLR4 KOs), including higher numbers of infiltrating CD3+ cells (P < 0.05, TLR4 and TLR9 KO), yet decreased infiltrating F4/80+ macrophages (P < 0.05, all groups). Furthermore, analysis of isolated macrophages revealed twofold reductions in VEGF-C (P < 0.01) and LYVE-1 (P < 0.05) mRNA from TLR2-deficient animals. Finally, TLR deficiency was associated with increased collagen type I deposition and increased transforming growth factor-β1 expression (P < 0.01, TLR4 and TLR9 KO), contributing to dermal fibrosis. In conclusion, TLR deficiency worsens tissue responses to lymphatic fluid stasis and is associated with decreased lymphangiogenesis, increased fibrosis, and reduced macrophage infiltration. These findings suggest a role for innate immune responses, including TLR signaling, in lymphatic repair and lymphedema pathogenesis.</div>
</front>
</TEI>
</pubmed>
</double>
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Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury

Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury

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