Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1
Dominika Nackiewicz,
Meixia Dan,
Madeleine Speck,
Samuel Z. Chow,
Yi-Chun Chen,
J. Andrew Pospisilik,
C. Bruce Verchere,
Jan A. Ehses
Affiliations
Dominika Nackiewicz
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
Meixia Dan
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
Madeleine Speck
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
Samuel Z. Chow
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
Yi-Chun Chen
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
J. Andrew Pospisilik
Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA
C. Bruce Verchere
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada; Department of Pathology and Laboratory Medicine, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada; Corresponding author
Jan A. Ehses
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada; Department of Health Sciences and Technology, Institute of Food, Nutrition, and Health, Swiss Federal Institute of Technology, ETH Zürich, Schwerzenbach CH-8603, Switzerland; Corresponding author
Summary: 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. : Diabetology; Immunology; Specialized Functions of Cells Subject Areas: Diabetology, Immunology, Specialized Functions of Cells
