Blockade but Not Overexpression of the Junctional Adhesion Molecule C Influences Virus-Induced Type 1 Diabetes in Mice

Selina Christen,Martin Holdener,Beat A Imhof,Kerstin Rose,Michel Aurrand-Lions,Matthias G Von Herrath,Ken Coppieters,Edith Hintermann,Urs Christen,Monika Bayer,Josef M Pfeilschifter,Kathrin Maedler

doi:10.1371/journal.pone.0054675

Abstract

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.

Highlights

The pathogenesis of Type 1 diabetes (T1D) is characterized by the destruction of insulin producing b-cells by autoaggressive lymphocytes invading the islets of Langerhans
We have demonstrated in the past that blockade of critical chemokines, such as CXCL10 (IP-10, IFNc-inducible protein of 10 kDa), results in the abrogation of T1D in the rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) model [1] indicating that cellular attraction to the islet of Langerhans is a critical step required for the subsequent destruction of insulin-producing b-cells
It has been shown that blockade of junctional adhesion molecule (JAM)-C, which plays an important role in the transmigration of leukocytes through the endothelial cell layer, reduces cellular infiltration and acinar cell necrosis in cerulein-induced pancreatitis [9]

Summary

Introduction

The pathogenesis of T1D is characterized by the destruction of insulin producing b-cells by autoaggressive lymphocytes invading the islets of Langerhans. Local expression of chemokines and subsequently the upregulation of a variety of adhesion molecules by endothelial cells facilitate the attraction and transmigration of leukocytes from the circulation to the islets. We have demonstrated in the past that blockade of critical chemokines, such as CXCL10 (IP-10, IFNc-inducible protein of 10 kDa), results in the abrogation of T1D in the RIP-LCMV model [1] indicating that cellular attraction to the islet of Langerhans is a critical step required for the subsequent destruction of insulin-producing b-cells. Blockade platelet endothelial cell adhesion molecule (PECAM-1) had no effect on T cell infiltration it was strongly expressed on islet vessels [6]. Mice lacking ICAM-1 are partially protected from cerulein-induced pancreatitis [7], but the administration of anti-ICAM-1 antibodies had only little effect [8]

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