Published online before print November 1, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061048

Accepted for publication August 21, 2007.

Article

Wound Healing Is Impaired in MyD88-Deficient Mice. A Role for MyD88 in the Regulation of Wound Healing by Adenosine A_2A Receptors

Lisa Macedo^*, Grace Pinhal-Enfield, Vera Alshits, Genie Elson, Bruce Neil Cronstein, and Samuel Joseph Leibovich^@

From the Department of Surgery,* Division of Plastic and Reconstructive Surgery, and the Department of Cell Biology and Molecular Medicine and the Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and the Department of Medicine, Division of Clinical Pharmacology, New York University School of Medicine, New York, New York

^@ To whom correspondence should be addressed. E-mail: leibovic{at}umdnj.edu.

	Abstract

Synergy between Toll-like receptor (TLR) and adenosine A_2A receptor (A_2AR) signaling switches macrophages from production of inflammatory cytokines such as tumor necrosis factor- to production of the angiogenic growth factor vascular endothelial growth factor (VEGF). We show in this study that this switch critically requires signaling through MyD88, IRAK4, and TRAF6. Macrophages from mice lacking MyD88 (MyD88^-/-) or IRAK4 (IRAK4^-/-) lacked responsiveness to TLR agonists and did not respond to A_2AR agonists by expressing VEGF. Suppression of TRAF6 expression with siRNA in RAW264.7 macrophages also blocked their response to TLR and A_2AR agonists. Excisional skin wounds in MyD88^-/- mice healed at a markedly slower rate than wounds in wild-type MyD88^+/+ mice, showing delayed contraction, decreased and delayed granulation tissue formation, and reduced new blood vessel density. Although macrophages accumulated to higher levels in MyD88^-/- wounds than in controls, expression of VEGF and HIF1- mRNAs was elevated in MyD88^+/+ wounds. CGS21680, an A_2AR agonist, promoted repair in MyD88^+/+ wounds and stimulated angiogenesis but had no significant effect on healing of MyD88^-/- wounds. These results suggest that the synergistic interaction between TLR and A_2AR signaling observed in vitro that switches macrophages from an inflammatory to an angiogenic phenotype also plays a role in wound healing in vivo.