title: Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model.
abstract: OBJECTIVE
  To investigate the presence and extent of inflammatory lymphangiogenesis in AD and determine the role of IL-4 in lymphatic proliferation in both K14-IL-4 Tg mouse model of AD and cultured human epidermal cells.
  
  
  METHODS
  Skin tissues from Tg mice were collected for immunostaining against PDPN, LYVE-1, CD11b and VEGF-C. The regulation of specific lymphatic biomarkers and growth factors were determined using qPCR and Western Blot analyses. Dermal lymphatic uptake and drainage were assessed using intradermal EB dye micro-injections. Total RNA from IL-4-stimulated HaCaT cells was analyzed in a PCR array to evaluate the regulation of lymphangiogenic-related genes.
  
  
  RESULTS
  Prominent dermal microvascular lymphangiogenesis occurs in the Tg mice, characterized by a significant increase in number and caliber of the vasculature. The extent of both lymphatic proliferation and drainage parallels the progression of lesion severity, as does the up-regulation of pro-lymphangiogenic factors VEGF-C, VEGFR-3, ANG-1, and ANG-2. IL-4-stimulated HaCaT cells express high levels of MCP-1, a strong macrophage chemo-attractant. Additionally, Tg mice show significantly increased number of dermal CD11b+ macrophages expressing VEGF-C in the skin.
  
  
  CONCLUSIONS
  Our results provide the first demonstration of inflammation-mediated lymphangiogenesis in AD and that IL-4 triggered macrophage recruitment may be closely linked to this phenomenon.
authors.affiliation: Department of Dermatology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Shi
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Chan
mesh_terms: D000818:Animals; D039481:CD11b Antigen; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042583:Lymphangiogenesis; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012259:Ribonuclease, Pancreatic / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis* / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C508598:IL4 protein, human; C467486:VEGFC protein, human; C555023:VPS51 protein, human; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; C467483:vascular endothelial growth factor C, mouse; D015847:Interleukin-4; D040321:Vascular Endothelial Growth Factor Receptor-3; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic