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Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression  Tsung-Lin Cheng, Chao-Han Lai, Po-Ku Chen, Chia-Fong Cho,

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Presentation on theme: "Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression  Tsung-Lin Cheng, Chao-Han Lai, Po-Ku Chen, Chia-Fong Cho,"— Presentation transcript:

1 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  Journal of Investigative Dermatology  Volume 135, Issue 6, Pages (June 2015) DOI: /jid Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 High-glucose environment inhibits the expression of thrombomodulin (TM) and Toll-like receptor 4 (TLR4) and reduces the production of soluble thrombomodulin (sTM) in both basal and injury-stimulated keratinocytes. (a) Western blot analysis of TM and TLR4 levels in human keratinocyte cell line (HaCaT) cells cultured with various sugar concentrations. Mannose as osmolarity control. (b) Determination of TM and TLR4 protein levels in cell lysates of primary keratinocytes isolated from diabetic patients. (c) Detection of the expression of the indicated proteins in HaCaT cells with or without scratch wound stimulation. GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Lys, lysate; Med, conditional medium. Representative figures from three independent experiments are shown. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Downregulated thrombomodulin (TM) expression, abrogated injury-triggered TM upregulation, and decreased soluble thrombomodulin (sTM) production in streptozotocin (STZ)-induced diabetic mouse skin. (a) Incision wounds in the back skin of control and STZ mice were examined. Sections from the control and STZ mice were stained with TMD1 antibody (green) and 4’,6 diamidino-2-phenylindole (DAPI; blue). The red dotted lines mark the hyperproliferative epithelium (HE). D, dermis. Scale bar=200μm. (b) Western blot analysis of TM levels in the skin samples from sodium citrate–treated (control) or STZ-treated mice. (c) Western blot analysis of sTM production in the conditional medium of primary cultured skin tissue. GST, glutathione S-transferase. Representative figures from three independent experiments are shown. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Human recombinant thrombomodulin domains 2 plus 3 (rTMD23) promotes wound recovery and Toll-like receptor 4 (TLR4) expression in high-glucose-cultured human HaCaT cells. (a) Wound recovery assay in high-glucose-cultured HaCaT cells treated with various doses of rTMD23 for 72hours. White dotted lines indicate the wound borders at the start of the assay. FBS, fetal bovine serum. (b) Quantitative representation of a. (c) Western blot analysis of TLR4 levels in high-glucose-cultured HaCaT cells treated with rTMD23 for 24hours at the indicated concentrations. (d) Quantitative representation of c. *P<0.05; **P<0.01, (n=3). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 Mouse recombinant thrombomodulin domains 2 plus 3 (rTMD23) promotes Toll-like receptor 4 (TLR4) expression and accelerates wound healing in streptozotocin (STZ) mouse skin. (a) Cutaneous wound healing assay in STZ mice treated with phosphate-buffered saline (PBS) or rTMD23 (125mgkg−1). Scale bar=4mm. (b) Quantitative representation of a (n=5). (c) Detection of TLR4 expression with western blotting analysis. The skin from the wound margin was sampled 24hours after the last rTMD23 injection. Representative results from three independent experiments are shown. (d) Quantitative representation of c. *P<0.05; **P<0.01. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 Mouse recombinant thrombomodulin domains 2 plus 3 (rTMD23) fails to promote wound recovery in Tlr4-deleted (TLR4del) mice. (a) Incision wound recovery analysis of the back skin of TLR4del mice treated with phosphate-buffered saline (PBS) or rTMD23 on days 2 and 3 after injury. Scale bar=5mm. (b) Quantitative representation of a (n=4). TLR, Toll-like receptor. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

7 Figure 6 High glucose triggers tumor necrosis factor-α (TNF-α) upregulation that decreases the expression of thrombomodulin (TM) and then reduces Toll-like receptor 4 (TLR4) protein levels. (a) Western blot analysis of TNF-α levels in keratinocytes cultured with the indicated glucose concentrations. (b) Analysis of TM protein expression after treatment with TNF-α antibody (Ab) at the indicated concentrations for 24hours. GAPDH, glyceraldehyde 3-phosphate dehydrogenase. (c) Western blot analysis of TM and TLR4 expression after treatment with TNF-α at the indicated concentrations for 24hours. (d) Detection of TLR4 expression in TM-stable silenced HaCaT cells. Representative figures from three independent experiments are shown. (e) Schematic model of high-glucose impairment of cutaneous wound healing via inhibition of TM and TLR4 expression. rTMD23, recombinant thrombomodulin domains 2 plus 3. shTM, short-hairpin RNA for targeting TM. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

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