NYMC Faculty Publications

Proinflammatory Signaling in Islet Β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes

Annie R. Piñeros, Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA.
Abhishek Kulkarni, Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA.
Hongyu Gao, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Kara S. Orr, Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA.
Lindsey Glenn, Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.
Fei Huang, Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA.
Yunlong Liu, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Maureen Gannon, Department of Medicine, Vanderbilt University and Department of Veterans Affairs, Tennessee Valley Authority, Nashville, TN, USA.
Farooq Syed, Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA.
Wenting Wu, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Cara M. Anderson, Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA.
Carmella Evans-Molina, Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush VA Medical Center, Indianapolis, IN, USA.
Marcia McDuffie, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Jerry L. Nadler, Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA.Follow
Margaret A. Morris, Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.
Raghavendra G. Mirmira, Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA. Electronic address: mirmira@uchicago.edu.
Sarah A. Tersey, Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA. Electronic address: stersey@uchicago.edu.

Author Type(s)

Faculty

DOI

10.1016/j.celrep.2022.111011

Journal Title

Cell Reports

First Page

111011

Document Type

Article

Publication Date

6-28-2022

Department

Medicine

Abstract

Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.

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