Accelerated wound healing in mice by local administration of sustained-release CpG oligodeoxynucleotide (136.4)

Abstract

Abstract Recent reports show that wounds in mice lacking MyD88 heal at a delayed rate, suggesting that the innate immune pathway can affect the healing process. Preliminary studies revealed that the kinetics of wound healing in TLR9 KO mice were also delayed when compared to congenic controls, suggesting that this activation pathway may contribute physiologically to wound healing. Synthetic oligodeoxynucleotides (ODN) expressing unmethylated CpG motifs mimic the ability of bacterial DNA to stimulate an innate immune response via TLR9. We incorporated CpG ODN into a vehicle (basement membrane extract) that slowly released bioactive ODN to wound sites. The effect of the ODN was then examined using a murine excisional skin biopsy model. Results show that CpG ODN treatment significantly accelerates wound repair in normal adult and aged mice (p < 0.0001 and p < 0.01, respectively). Consistent with these effects being mediated by CpG signaling via TLR9, no effect was observed in TLR9 KO mice. Histologic studies indicate that CpG treatment promotes local accumulation of macrophages, increases production of VEGF, and accelerates neovascularization, resulting in accelerated granulation and wound closure in wildtype (but not TLR9 KO mice, p < 0.01). Current findings suggest that immunostimulatory oligonucleotides may represent a novel, inexpensive, safe and effective means of improving wound repair.