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

Fingerprint

Transendothelial and Transepithelial Migration
Bile Acids and Salts
Arthritis
Heparin
T-Lymphocytes
Endothelial Cells
Intercellular Adhesion Molecule-1
Anti-Inflammatory Agents
Joints
Selectins
P-Selectin
Deoxycholic Acid
Experimental Arthritis
Membrane Transport Proteins
GTP Phosphohydrolases
Low Molecular Weight Heparin
Vascular Endothelium
Anticoagulants
Biological Availability
Oral Administration

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Intracellular delivery of desulfated heparin with bile acid conjugation alleviates T cell-mediated inflammatory arthritis via inhibition of RhoA-dependent transcellular diapedesis. / Kang, Jin Hee; Hwang, Seung Rim; Sung, Shijin; Jang, Ji Ae; Alam, Md Mahmudul; Sa, Keum Hee; Kim, Sang Yeob; Kim, In-San; Byun, Young Ro; Kang, Young Mo.

In: Journal of Controlled Release, Vol. 183, No. 1, 10.06.2014, p. 9-17.

Research output: Contribution to journalArticle

Kang, Jin Hee ; Hwang, Seung Rim ; Sung, Shijin ; Jang, Ji Ae ; Alam, Md Mahmudul ; Sa, Keum Hee ; Kim, Sang Yeob ; Kim, In-San ; Byun, Young Ro ; Kang, Young Mo. / Intracellular delivery of desulfated heparin with bile acid conjugation alleviates T cell-mediated inflammatory arthritis via inhibition of RhoA-dependent transcellular diapedesis. In: Journal of Controlled Release. 2014 ; Vol. 183, No. 1. pp. 9-17.
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AU - Sung, Shijin

AU - Jang, Ji Ae

AU - Alam, Md Mahmudul

AU - Sa, Keum Hee

AU - Kim, Sang Yeob

AU - Kim, In-San

AU - Byun, Young Ro

AU - Kang, Young Mo

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N2 - 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.

AB - 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.

KW - Bile acid conjugation

KW - Desulfation

KW - Endothelial cell

KW - Inflammatory arthritis

KW - Low molecular weight heparin

KW - T cell

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