Decreased Macrophage Number and Activation Lead to Reduced Lymphatic Vessel Formation and Contribute to Impaired Diabetic Wound Healing

Am J Pathol. 2007 Apr;170(4):1178-91. doi: 10.2353/ajpath.2007.060018.

Abstract

Impaired wound healing is a common complication of diabetes. Although it is well known that both macrophages and blood vessels are critical to wound repair, the role of wound-associated lymphatic vessels has not been well investigated. We report that both the presence of activated macrophages and the formation of lymphatic vessels are rate-limiting to the healing of diabetic wounds. We have previously shown that macrophages contribute to the lymphatic vessels that form during the acute phase of corneal wound healing. We now demonstrate that this is a general phenomenon; cells that co-stain for the macrophage marker F4/80 and the lymphatic markers LYVE-1 (lymphatic vascular endothelium hyaluronate receptor) and podoplanin contribute to lymphatic vessels in full-thickness wounds. LYVE-1-positive lymphatic vessels and CD31-positive blood vessels were significantly reduced in corneal wound healing in diabetic mice (db/db) (P < 0.02) compared with control (db/+) mice. Glucose treatment of control macrophages led to the down-regulation of the lymphatic-specific receptor VEGFR3 and its ligands, vascular endothelial growth factor-C and -D (VEGF-C, -D). Interleukin-1beta stimulation rescued diabetic macrophage function; application of interleukin-1beta-treated db/db-derived macrophages to wounds in db/db mice induced lymphatic vessel formation and accelerated wound healing. These observations suggest a potential therapeutic approach for healing wounds in diabetic patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Differentiation / analysis
  • Bone Marrow Transplantation / methods
  • Cornea / chemistry
  • Cornea / pathology
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Gene Expression / drug effects
  • Glucose / pharmacology
  • Glycoproteins / analysis
  • Immunohistochemistry
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Interleukin-1beta / pharmacology
  • Lymphangiogenesis / drug effects
  • Lymphatic Vessels / chemistry
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / pathology*
  • Macrophages / chemistry
  • Macrophages / pathology*
  • Macrophages / transplantation
  • Male
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Platelet Endothelial Cell Adhesion Molecule-1 / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin / drug effects
  • Skin / pathology
  • Skin / physiopathology
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Wound Healing / drug effects
  • Wound Healing / physiology*

Substances

  • Antigens, Differentiation
  • Glycoproteins
  • Interleukin-1beta
  • Membrane Transport Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Xlkd1 protein, mouse
  • monocyte-macrophage differentiation antigen
  • Vascular Endothelial Growth Factor Receptor-3
  • Glucose