Published online before print June 15, 2009

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(American Journal of Pathology. 2009;175:132-147.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081002

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

Itamar Goren^*, Nadine Allmann^*, Nir Yogev, Christoph Schürmann^*, Andreas Linke^*, Martin Holdener^*, Ari Waisman, Josef Pfeilschifter^* and Stefan Frank^*

From the Pharmazentrum Frankfurt/ZAFES,^* Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; and the I. Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Mainz, Germany

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-1β, and cyclooxygenase-2, paralleled by unaltered levels of bioactive transforming growth factor-β1. 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.

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