A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes

Am J Pathol. 2009 Jul;175(1):132-47. doi: 10.2353/ajpath.2009.081002. Epub 2009 Jun 15.


Whether the wound macrophage is a key regulatory inflammatory cell type in skin repair has been a matter of debate. A transgenic mouse model mediating inducible macrophage depletion during skin repair has not been used to date to address this question. Here, we specifically rendered the monocyte/macrophage leukocyte lineage sensitive to diphtheria toxin by expressing the lysozyme M promoter-driven, Cre-mediated excision of a transcriptional STOP cassette from the simian DT receptor gene in mice (lysM-Cre/DTR). Application of diphtheria toxin to lysM-Cre/DTR mice led to a rapid reduction in both skin tissue and wound macrophage numbers at sites of injury. Macrophage-depleted mice revealed a severely impaired wound morphology and delayed healing. In the absence of macrophages, wounds were re-populated by large numbers of neutrophils. Accordingly, macrophage-reduced wound tissues exhibited the increased and prolonged persistence of macrophage inflammatory protein-2, macrophage chemoattractant protein-1, interleukin-1beta, and cyclooxygenase-2, paralleled by unaltered levels of bioactive transforming growth factor-beta1. Altered expression patterns of vascular endothelial growth factor on macrophage reduction were associated with a disturbed neo-vascularization at the wound site. Impaired wounds revealed a loss of myofibroblast differentiation and wound contraction. Our data in the use of lysM-Cre/DTR mice emphasize the pivotal function of wound macrophages in the integration of inflammation and cellular movements at the wound site to enable efficient skin repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Lineage / immunology*
  • Diphtheria Toxin / toxicity
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Inflammation / immunology*
  • Keratinocytes / metabolism
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Transgenic
  • Muramidase / immunology
  • Muramidase / metabolism*
  • Neovascularization, Physiologic / immunology*
  • Poisons / toxicity
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / metabolism
  • Wound Healing / immunology*


  • Diphtheria Toxin
  • Poisons
  • Transforming Growth Factor beta
  • Muramidase
  • lysozyme M, mouse