Thrombomodulin promotes diabetic wound healing by regulating toll-like receptor 4 expression

Tsung Lin Cheng, Chao Han Lai, Po Ku Chen, Chia Fong Cho, Yun Yan Hsu, Kuan Chieh Wang, Wei Ling Lin, Bi Ing Chang, Shi Kai Liu, Yu Ting Wu, Chao Kai Hsu, Guey Yueh Shi, Hua Lin Wu

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Keratinocyte-expressed thrombomodulin (TM) and the released soluble TM (sTM) have been demonstrated to promote wound healing. However, the effects of high glucose on TM expression in keratinocytes and the role of TM in diabetic ulcer remain unclear. In this study, we demonstrated that expressions of TM and Toll-like receptor 4 (TLR4) were both downregulated in high-glucose cultured human keratinocytes and in skin keratinocytes of diabetic patients. In addition, the wound-triggered upregulation of TM and sTM production was abolished in both high-glucose cultured human keratinocytes and streptozotocin-induced diabetic mouse skin. Furthermore, supplementation of recombinant sTM could increase TLR4 expression and promote cutaneous wound healing in both high-glucose cultured human keratinocytes and diabetic mice. However, in Tlr4-deleted mice, which exhibited delayed wound healing, the therapeutic benefit of recombinant sTM was abrogated. Moreover, our results showed that tumor necrosis factor-α (TNF-α) expression in keratinocytes was dose-dependently upregulated by glucose, and TNF-α treatment downregulated the expression of TM and TLR4. Taken together, high-glucose environment reduces the expression of TM and TLR4 in keratinocytes possibly through the action of TNF-α, and recombinant sTM can increase the TLR4 expression and promote wound healing under diabetic condition.

Original languageEnglish
Pages (from-to)1668-1675
Number of pages8
JournalJournal of Investigative Dermatology
Volume135
Issue number6
DOIs
Publication statusPublished - 2015 Jan 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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