Study on the role of the lectin-like domain of thrombomodulin in cutaneous wound healing

Abstract

Thrombomodulin (TM) is a type I transmembrane glycoprotein that is predominantly expressed on the surface of vascular endothelial cells and some other cells such as keratinocytes and macrophages Previous studies have demonstrated that TM is highly expressed in keratinocytes during wound healing Previous reports have indicated that the N-terminal lectin-like domain of TM (TM domain 1 TMD1) plays a role in inhibition of inflammatory reaction Cutaneous wound healing consists of three stages including inflammatory phase tissue proliferation phase and tissue remodeling phase Macrophages represent one of the most abundant inflammatory cell types during all stages of tissue repair Macrophages not only cleanse foreign bacteria and particles but also secrete pro-inflammatory mediators and numerous growth factors contributing to tissue growth High mobility group box protein 1 (HMGB1) is a nuclear DNA binding protein which can be secreted as a pro-inflammatory cytokine from nucleus to cytosol or out of various cells stimulated with pro-inflammatory cytokines In this study we demonstrated that the wound healing rate was slower in mice lacking the lectin-like domain of TM (TMLeD/LeD mice) than in wild-type mice in cutaneous wound healing assay in vivo Furthermore peritoneal macrophages from TMLeD/LeD mice had higher gene expression levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) Secretion of HMGB1 in cytosol and conditioned medium was higher in macrophages from TMLeD/LeD mice after stimulation with tumor necrosis factor-? (TNF-?) In addition macrophage and neutrophil infiltration were increased at the wound sites of TMLeD/LeD mice on day 3 after wounding and so did the protein expression of IL-6 interleukin-1 beta (IL-1β) and MCP-1 Finally local administration of recombinant TMD1 (rTMD1) to the wound site significantly improved the wound healing in TMLeD/LeD mice and streptozotocin (STZ)-induced diabetic mice In addition rTMD1 inhibited pro-inflammatory cytokine IL-6 and IL-1β production and decreased neutrophil and macrophage infiltration at the wound site in diabetic mice In summary we found that TMD1 functions as a key regulator of inflammatory reaction in cutaneous wound healing and has therapeutic potential for the treatment for cutaneous wounds

Date of Award	2015 Jul 30
Original language	English
Supervisor	Hua-Lin Wu (Supervisor)