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


Authors: Zampell, J. C.; Elhadad, S.; Avraham, T.; Weitman, E.; Aschen, S.; Yan, A.; Mehrara, B. J.
Article Title: Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury
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. © 2012 the American Physiological Society.
Keywords: signal transduction; controlled study; protein expression; gene deletion; nonhuman; protein function; cd3 antigen; cell proliferation; protein analysis; animal cell; mouse; animals; mice; mice, knockout; mus; edema; gene expression; cell infiltration; interleukin 13; interleukin 4; animal experiment; animal model; inflammation; histology; animalia; collagen type 1; vasculotropin c; lymphangiogenesis; lymphedema; fibrosis; lymphatic vessels; vascular endothelial growth factor c; podoplanin; toll like receptor 4; th2 cell; gamma interferon; collagen; transforming growth factor beta1; innate immunity; immunity, innate; th1 cell; macrophage; macrophages; cd3+ t lymphocyte; loss of function mutation; glycoproteins; toll like receptor 2; cd45 antigen; toll-like receptor 9; toll-like receptor 4; toll like receptor 9; skin fibrosis; endogenous danger signals; interstitial fluid; leukemic infiltration; toll-like receptor 2
Journal Title: American Journal of Physiology - Cell Physiology
Volume: 302
Issue: 4
ISSN: 0363-6143
Publisher: American Physiological Society  
Date Published: 2012-02-01
Start Page: C709
End Page: C719
Language: English
DOI: 10.1152/ajpcell.00284.2011
PROVIDER: scopus
PMCID: PMC3287358
PUBMED: 22049214
DOI/URL:
Notes: --- - "Export Date: 1 March 2012" - "CODEN: AJPCD" - "Source: Scopus"
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MSK Authors
  1. Sonia Elhadad
    10 Elhadad
  2. Babak Mehrara
    295 Mehrara
  3. Tomer Avraham
    33 Avraham
  4. Jamie Christine Zampell
    29 Zampell
  5. Alan Yan
    20 Yan
  6. Evan Scott Weitman
    18 Weitman
  7. Seth Aschen
    13 Aschen