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Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes.
Lee, Hugo; Lee, Yong-Syu; Harenda, Quincy; Pietrzak, Stefan; Oktay, Hülya Zeynep; Schreiber, Sierra; Liao, Yian; Sonthalia, Shreyash; Ciecko, Ashley E; Chen, Yi-Guang; Keles, Sunduz; Sridharan, Rupa; Engin, Feyza.
Afiliación
  • Lee H; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Lee YS; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Harenda Q; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Pietrzak S; Department of Cell and Regenerative Biology, Wisconsin Institute for Discovery, Madison, WI 53706, USA.
  • Oktay HZ; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Schreiber S; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Liao Y; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Sonthalia S; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
  • Ciecko AE; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Chen YG; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Keles S; Department of Biostatistics & Medical Informatics and Department of Statistics, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53705, USA.
  • Sridharan R; Department of Cell and Regenerative Biology, Wisconsin Institute for Discovery, Madison, WI 53706, USA.
  • Engin F; Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA; Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53705,
Cell Metab ; 31(4): 822-836.e5, 2020 04 07.
Article en En | MEDLINE | ID: mdl-32220307
Immune-mediated destruction of insulin-producing ß cells causes type 1 diabetes (T1D). However, how ß cells participate in their own destruction during the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in ß cells of non-obese diabetic (NOD) mice by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of ß cells, resulting in substantially reduced islet immune cell infiltration and ß cell apoptosis. Single-cell and whole-islet transcriptomics analyses of immature ß cells revealed remarkably diminished expression of ß cell autoantigens and MHC class I components, and upregulation of immune inhibitory markers. IRE1α-deficient mice exhibited significantly fewer cytotoxic CD8+ T cells in their pancreata, and adoptive transfer of their total T cells did not induce diabetes in Rag1-/- mice. Our results indicate that inducing ß cell dedifferentiation, prior to insulitis, allows these cells to escape immune-mediated destruction and may be used as a novel preventive strategy for T1D in high-risk individuals.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Diabetes Mellitus Tipo 1 / Endorribonucleasas / Células Secretoras de Insulina / Desdiferenciación Celular / Respuesta de Proteína Desplegada Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Diabetes Mellitus Tipo 1 / Endorribonucleasas / Células Secretoras de Insulina / Desdiferenciación Celular / Respuesta de Proteína Desplegada Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos