Intracellular delivery of desulfated heparin with bile acid conjugation alleviates T cell-mediated inflammatory arthritis via inhibition of RhoA-dependent transcellular diapedesis

Jin Hee Kang, Seung Rim Hwang, Shijin Sung, Ji Ae Jang, Md Mahmudul Alam, Keum Hee Sa, Sang Yeob Kim, In San Kim, Young Ro Byun, Young Mo Kang

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Heparin has a potential regulatory role in inflammatory diseases. However, the anticoagulant activity and poor oral bioavailability of heparin limit its use as an anti-inflammatory agent. Conjugation of bis-deoxycholic acid to 6-O-desulfated low molecular weight heparin (6DSHbD) was efficiently internalized by activated endothelial cells via a 2-step model, in which heparin attaches to adhesion molecules that facilitate accessibility of the bile acid conjugate to membrane transporters. The critical role of P-selectin during endothelial cell uptake of 6DSHbD by arthritic tissue was confirmed in p-selectin-/- arthritic mice. Intracellular 6DSHbD inhibited transcellular diapedesis of T cells through activated endothelial cells and impaired both the formation of ICAM-1-rich docking structures at the T cell contact surface and subsequent cytoskeletal rearrangement. Furthermore, 6DSHbD blocked activation of RhoA-GTPase and phosphorylation of ezrin/radixin/moesin induced by ICAM-1 cross-linking on activated endothelial cells, thereby impairing lymphocyte transcellular transmigration. After oral administration 6DSHbD was preferentially delivered to inflamed joint tissue, particularly in and around post-capillary venular endothelium and inhibited effector T cell homing to arthritic joints. Aggravation of collagen-induced arthritis conferred by the transfer of effector T cells was suppressed by oral 6DSHbD. Thus, intracellular heparin exerts anti-inflammatory effects through the inhibition of RhoA-dependent transendothelial recruitment of T cells and may have applications in the treatment of chronic inflammatory arthritis.

Original languageEnglish
Pages (from-to)9-17
Number of pages9
JournalJournal of Controlled Release
Volume183
Issue number1
DOIs
Publication statusPublished - 2014 Jun 10
Externally publishedYes

Keywords

  • Bile acid conjugation
  • Desulfation
  • Endothelial cell
  • Inflammatory arthritis
  • Low molecular weight heparin
  • T cell

ASJC Scopus subject areas

  • Pharmaceutical Science

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