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

Authors

• 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

Keywords

CP: Metabolism, NOD mouse, immune checkpoint, immunology, insulin, islet, pancreas, single-cell RNA sequencing, type 1 diabetes

Disciplines

Medicine and Health Sciences

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.

Recommended Citation

Piñeros, A. R., Kulkarni, A., Gao, H., Orr, K. S., Glenn, L., Huang, F., Liu, Y., Gannon, M., Syed, F., Wu, W., Anderson, C. M., Evans-Molina, C., McDuffie, M., Nadler, J. L., Morris, M. A., Mirmira, R. G., & Tersey, S. A. (2022). Proinflammatory Signaling in Islet Β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes. Cell Reports, 39 (13), 111011. https://doi.org/10.1016/j.celrep.2022.111011