title: Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes.
abstract: The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.
authors.affiliation: Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ziolkowski
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Popp
authors.forename: Craig
authors.initials: C
authors.lastname: Freeman
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
authors.forename: Charmaine J
authors.initials: CJ
authors.lastname: Simeonovic
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000276:immunology / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D017382:Reactive Oxygen Species; D000099175:Heparanase