TY - JOUR
T1 - High-mobility group box-1-Toll-Like receptor 4 axis mediates the recruitment of endothelial progenitor cells in alkali-induced corneal neovascularization
AU - Yang, Shuai
AU - Yang, Tian Shu
AU - Wang, Fang
AU - Su, Shao Bo
N1 - Funding Information:
This project was supported by grants from the National Natural Science Foundation of China ( 31170861 ).
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/7/20
Y1 - 2015/7/20
N2 - 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 4 days 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.
AB - 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 4 days 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.
KW - EPCs
KW - HMGB1
KW - Neovascularization
KW - SDF-1
KW - TLR4
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U2 - 10.1016/j.intimp.2015.07.013
DO - 10.1016/j.intimp.2015.07.013
M3 - Article
C2 - 26202806
AN - SCOPUS:84937220170
SN - 1567-5769
VL - 28
SP - 450
EP - 458
JO - International immunopharmacology
JF - International immunopharmacology
IS - 1
M1 - 3796
ER -