Can CD44 Be a Mediator of Cell Destruction? The Challenge of Type 1 Diabetes.

Nathalie Assayag-Asherie,Ariel Ginzberg,Talya Weiss,Elimelech Okon,Marika Bogdani,Lola Weiss,Sharon Perles,Pamela Johnson,Itamar Raz,David Naor,Eva A Turley,Dror Sever,Lora Eshkar Sebban,Marc S Horwitz

doi:10.1371/journal.pone.0143589

Abstract

CD44 is a multi-functional receptor with multiple of isoforms engaged in modulation of cell trafficking and transmission of apoptotic signals. We have previously shown that injection of anti-CD44 antibody into NOD mice induced resistance to type 1 diabetes (T1D). In this communication we describe our efforts to understand the mechanism underlying this effect. We found that CD44-deficient NOD mice develop stronger resistance to T1D than wild-type littermates. This effect is not explained by the involvement of CD44 in cell migration, because CD44-deficient inflammatory cells surprisingly had greater invasive potential than the corresponding wild type cells, probably owing to molecular redundancy. We have previously reported and we show here again that CD44 expression and hyaluronic acid (HA, the principal ligand for CD44) accumulation are detected in pancreatic islets of diabetic NOD mice, but not of non-diabetic DBA/1 mice. Expression of CD44 on insulin-secreting β cells renders them susceptible to the autoimmune attack, and is associated with a diminution in β-cells function (e.g., less insulin production and/or insulin secretion) and possibly also with an enhanced apoptosis rate. The diabetes-supportive effect of CD44 expression on β cells was assessed by the TUNEL assay and further strengthened by functional assays exhibiting increased nitric oxide release, reduced insulin secretion after glucose stimulation and decreased insulin content in β cells. All these parameters could not be detected in CD44-deficient islets. We further suggest that HA-binding to CD44-expressing β cells is implicated in β-cell demise. Altogether, these data agree with the concept that CD44 is a receptor capable of modulating cell fate. This finding is important for other pathologies (e.g., cancer, neurodegenerative diseases) in which CD44 and HA appear to be implicated.

Highlights

Type 1 diabetes (T1D) is in many aspects a representative inflammatory autoimmune disease, which can be used as a model for unveiling the mechanism of action underlying chronic inflammation in general
We analyzed by Western blot the caspase-3 activity in the cell extracts of pancreatic islets derived from WT and CD44-deficient NOD pre-diabetic females, and observed an enhanced enzymatic activity in the cell extracts of WT pancreatic islets when compared with those of CD44-deficient (Fig 3A). To substantiate this initial finding, and assure that caspase-3 activity signal is related to insulin-producing β cells, we evaluated the number of apoptotic β cells in the pancreas of prediabetic normoglycemic WT and CD44-deficient NOD females (10-weeks-old)
It should be indicated that insulin secretion may be a CD44-dependent event since CD44-deficient β cells secrete basically less insulin than corresponding WT cells (Fig 4B)

Summary

Introduction

Type 1 diabetes (T1D) is in many aspects a representative inflammatory autoimmune disease, which can be used as a model for unveiling the mechanism of action underlying chronic inflammation in general. Most if not all investigators agree that this disease displays clear adaptive and innate autoimmune parameters, leading to destruction of the insulin-secreting β cells, e.g., by reactive oxygen species (ROS), such as nitric oxide (NO)[1,2,3,4,5,6].the intra-islet invasion mechanisms by pre-diabetic inflammatory cells and the process underlying the demise of β cells undergoing attack by the immune system have yet to be understood. Less is known about the role of CD44 in this pathology [13]

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