High-mobility group box-1-Toll-Like receptor 4 axis mediates the recruitment of endothelial progenitor cells in alkali-induced corneal neovascularization

Shuai Yang, Tian Shu Yang, Fang Wang, Shao Bo Su

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number3796
Pages (from-to)450-458
Number of pages9
JournalInternational immunopharmacology
Volume28
Issue number1
DOIs
StatePublished - Jul 20 2015
Externally publishedYes

Keywords

  • EPCs
  • HMGB1
  • Neovascularization
  • SDF-1
  • TLR4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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