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.