title: Deficiency in type I interferon signaling prevents the early interferon-induced gene signature in pancreatic islets but not type 1 diabetes in NOD mice.
abstract: Type I interferons (IFNs) have been implicated in the initiation of islet autoimmunity and development of type 1 diabetes. To directly test their involvement, we generated NOD mice deficient in type I IFN receptors (NOD.IFNAR1(-/-)). Expression of the type I IFN-induced genes Mx1, Isg15, Ifit1, Oas1a, and Cxcr4 was detectable in NOD islets as early as 1 week of age. Of these five genes, expression of Isg15, Ifit1, Oas1a, and Mx1 peaked at 3-4 weeks of age, corresponding with an increase in Ifnα mRNA, declined at 5-6 weeks of age, and increased again at 10-14 weeks of age. Increased IFN-induced gene expression was ablated in NOD.IFNAR1(-/-) islets. Loss of Toll-like receptor 2 (TLR2) resulted in reduced islet expression of Mx1 at 2 weeks of age, but TLR2 or TLR9 deficiency did not change the expression of other IFN-induced genes in islets compared with wild-type NOD islets. We observed increased β-cell major histocompatibility complex class I expression with age in NOD and NOD.IFNAR1(-/-) mice. NOD.IFNAR1(-/-) mice developed insulitis and diabetes at a similar rate to NOD controls. These results indicate type I IFN is produced within islets in young mice but is not essential for the initiation and progression of diabetes in NOD mice.
authors.affiliation: St. Vincent's Institute, Fitzroy, Australia.
authors.forename: Hong Sheng
authors.initials: HS
authors.lastname: Quah
authors.forename: Socorro
authors.initials: S
authors.lastname: Miranda-Hernandez
authors.forename: Aimee
authors.initials: A
authors.lastname: Khoo
authors.forename: Ashley
authors.initials: A
authors.lastname: Harding
authors.forename: Stacey
authors.initials: S
authors.lastname: Fynch
authors.forename: Lorraine
authors.initials: L
authors.lastname: Elkerbout
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Brodnicki
authors.forename: Alan G
authors.initials: AG
authors.lastname: Baxter
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007370:Interferon Type I / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology
chemical_list: D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D053633:Receptor, Interferon alpha-beta