Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1

• Published in: iScience Vol. 23; no. 1; p. 100775
• Main Authors: Nackiewicz, Dominika, Dan, Meixia, Speck, Madeleine, Chow, Samuel Z., Chen, Yi-Chun, Pospisilik, J. Andrew, Verchere, C. Bruce, Ehses, Jan A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.01.2020; Elsevier
• Subjects: Diabetology; Immunology; Specialized Functions of Cells; Diabetology; Immunology; Specialized Functions of Cells
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.100775

Macrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages had increased Igf1 expression, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet insulin-like growth factor-1 (IGF-1) production. Adoptive transfer experiments showed that macrophages can maintain insulin secretion in vivo following beta-cell death with no effects on islet cell turnover. IGF-1 neutralization during STZ treatment decreased insulin secretion without affecting islet cell apoptosis or proliferation. Interestingly, high-fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages from db/db mice also expressed decreased proinflammatory cytokines and increased Igf1 mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia. [Display omitted] •Macrophages are a major source of IGF-1 protein within mouse pancreatic islets•Post-beta-cell death islet macrophages shift to a reparative state•Beta-cell death causes macrophage transcriptome changes consistent with efferocytosis•This change can occur even in the presence of HFD feeding or severe hyperglycemia Diabetology; Immunology; Specialized Functions of Cells