title: High-mobility group box-1-Toll-Like receptor 4 axis mediates the recruitment of endothelial progenitor cells in alkali-induced corneal neovascularization.
abstract: Endothelial progenitor cells (EPCs) promote both physiological and pathological neovascularization. Recently we found high-mobility group box-1 (HMGB1)-Toll-like receptor 4 (TLR4) signaling pathway promotes corneal neovascularization (CNV) induced by alkali in a mouse model. However, it is still unclear whether HMGB1-TLR4 promotes the mobility of EPCs. In this study, we explored the role of HMGB1-TLR4 signaling in EPC recruitment by modulating the activity of HMGB1-TLR4 signaling in the corneas of alkali-induced CNV mouse model. The level of EPC recruitment in injured corneas, as detected by flow cytometry, is increased and reaches the peak level 4days after injury. Activating TLR4 with exogenous HMGB1 or LPS enhances the EPC recruitment, whereas inhibiting the activity of HMGB1 and TLR4 with A-box (selective HMGB1 antagonist) or LPS-RS (selective TLR4 antagonist), respectively, reverses this phenotype. Moreover, the TLR4 mediated EPC recruitment is associated with up-regulation of stromal cell-derived factor-1 (SDF-1), a pivotal cytokine in EPC mobilization. Activation of TLR4 or HMGB1 leads to increased SDF-1 expression, while blocking TLR4 or HMGB1 inhibits the expression of SDF-1. Topical administration of AMD-3100, an antagonist of SDF-1 receptor, suppresses the TLR4-mediated EPC recruitment and ameliorates CNV. Our results indicated that activation of HMGB1-TLR4 signaling pathway promotes EPC recruitment in CNV, at least in part through up-regulation of SDF-1.
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Tian-Shu
authors.initials: TS
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: 18917683335@163.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: shaobosu@yahoo.com.
authors.forename: Shao-Bo
authors.initials: SB
authors.lastname: Su
mesh_terms: D000818:Animals; D002057:Burns, Chemical / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D003315:Cornea / Q000187:drug effects / Q000378:metabolism; D065306:Corneal Injuries / Q000139:chemically induced / Q000378:metabolism*; D016510:Corneal Neovascularization / Q000139:chemically induced / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000502:physiology*; D005126:Eye Burns / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D012972:Sodium Hydroxide; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D012972:Sodium Hydroxide
keywords: EPCs; HMGB1; Neovascularization; SDF-1; TLR4