title: Can CD44 Be a Mediator of Cell Destruction? The Challenge of Type 1 Diabetes.
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.
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Assayag-Asherie
authors.affiliation: Department of Endocrinology, Hadassah University Hospital, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Sever
authors.affiliation: Matrix Biology Program, Benaroya Research Institute, Seattle, WA, United States of America.
authors.forename: Marika
authors.initials: M
authors.lastname: Bogdani
authors.affiliation: Matrix Biology Program, Benaroya Research Institute, Seattle, WA, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Johnson
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Talya
authors.initials: T
authors.lastname: Weiss
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Ginzberg
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Perles
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Hospital Ein Kerem, Hebrew University, Jerusalem, 91120 Israel.
authors.forename: Lola
authors.initials: L
authors.lastname: Weiss
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Lora Eshkar
authors.initials: LE
authors.lastname: Sebban
authors.affiliation: London Regional Cancer Center, University of Western Ontario, London, ON, Canada.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Turley
authors.affiliation: LEM laboratories Science Park, Rehovot, Israel.
authors.forename: Elimelech
authors.initials: E
authors.lastname: Okon
authors.affiliation: Diabetes Unit, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Naor
mesh_terms: D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D002465:Cell Movement; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051379:Mice
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D005947:Glucose