The effect of recombinant thrombomodulin domains in macrophage polarization

Abstract

Macrophages can be induced to polarize to classically activated (M1) macrophages and alternatively activated (M2) macrophages by Th1 and Th2 cytokines respectively M1 macrophages promote phagocytosis and inflammatory response whereas M2 macrophages can secret anti-inflammatory cytokines and angiogenic factors for tissue repair It has been reported that persistent inflammation and increased M1 macrophages in wound area might contribute to the delayed wound healing in diabetic wounds suggesting that functional and phenotypic switch of macrophages is a very important regulating process in cutaneous wound healing Thrombomodulin (TM) a type I transmembrane glycoprotein contains five functional domains including a N-terminal C-type lectin-like domain a six-repeated epidermal growth factor (EGF)-like domain a serine/threonine-rich domain a transmembrane domain and a cytoplasmic domain Previous research in our lab demonstrated that expression of TM in keratinocytes is involved in keratinocyte differentiation and wound healing However the function of recombinant TM domains in macrophage polarization remains unknown In this study we demonstrated that mouse peritoneal macrophages could be polarized to M2 phenotypes by treatment with recombinant EGF-like domain plus serine/threonine-rich domain of TM (rTMD23) The phosphorylation of signal transducer and activator of transcription (STAT) 1 induced by interferon-? was inhibited by rTMD23 whereas the phosphorylation of STAT6 and STAT3 induced by interlukin-4 and interlukin-10 were enhanced by rTMD23 rTMD23 also enhanced CD206 expression a marker for M2 phenotype by increase of c-Myc expression in macrophages Furthermore local administration of rTMD23 to the cutaneous wound opening decreased the levels of inflammatory cytokines promoted angiogenesis increased the proportion of M2 macrophages in the wound area and accelerated wound closure in mice In conclusion we demonstrate that rTMD23 can accelerate wound healing by inducing M2 macrophage polarization and suppression of inflammatory response in wound opening

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