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

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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

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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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