Journal Article

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

Elisabeth Eppler, Ranit Maor-Cahn, Francoise Homo-Delarche, Pascale Ribaux, John A. Pospisilik, Marten K.J. Schneider, Helga Ellingsgaard, Xavier Gueripel, Manfred Reinecke, Jan A. Ehses, Adriano Fontana, Marc Y. Donath, Aurel Perren, Gregoire Biollaz

2007

Overview

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes Jan A. Ehses 1 , Aurel Perren 2 , Elisabeth Eppler 3 , Pascale Ribaux 4 , John A. Pospisilik 5 , Ranit Maor-Cahn 1 , Xavier Gueripel 2 , Helga Ellingsgaard 1 , Marten K.J. Schneider 6 , Gregoire Biollaz 7 , Adriano Fontana 7 , Manfred Reinecke 3 , Francoise Homo-Delarche 8 and Marc Y. Donath 1 1 Division of Endocrinology and Diabetes and Center for Integrated Human Physiology, University Hospital of Zürich, Zürich, Switzerland 2 Department of Pathology, University Hospital of Zürich, Zürich, Switzerland 3 Division of Neuroendocrinology, Institute of Anatomy, University of Zürich, Zürich, Switzerland 4 Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland 5 Institute of Molecular Biotechnology, Austrian Academy of Science, Vienna, Austria 6 Laboratory for Transplantation Immunology, University Hospital of Zürich, Zürich, Switzerland 7 Division of Clinical Immunology, University Hospital of Zürich, Zürich, Switzerland 8 Unité mixte de recherches 7059, National Center for Scientific Research, Paris 7 University/D. Diderot, Paris, France Address correspondence and reprint requests to Dr. Jan A. Ehses, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: jan.ehses{at}usz.ch . Or to Dr. Marc Y. Donath, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland. E-mail: marc.donath{at}usz.ch Abstract Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat–fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat–fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1α. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and β-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic α-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes. AEC, 3-amino-9-ethylcarbazole ECM, extracellular matrix FITC, fluorescein isothiocyanate G-CSF, granulocyte colony-stimulating factor IL, interleukin IP-10, interferon-inducible protein 10 MHC, major histocompatibility complex MIP, macrophage inflammatory protein Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 19 June 2007. DOI: 10.2337/db06-1650. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 21, 2007. Received November 26, 2006. DIABETES

• Publisher: American Diabetes Association
• Subject: Aged / Aged, 80 and over / Antibodies / Antigens, CD - analysis / Atherosclerosis / Biological and medical sciences / Care and treatment / Cell Count / Chemokines / Cloning / Cytokines / Diabetes / Diabetes Mellitus, Type 2 - pathology / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / Granulocytes / Health aspects / Histology / HLA-B Antigens - analysis / Humans / Immune system / Insulin resistance / Islets of Langerhans - immunology / Islets of Langerhans - pathology / Macrophages / Macrophages - immunology / Macrophages - pathology / Male / Medical sciences / Middle Aged / Neoplasms - pathology / Neoplasms - surgery / Neutrophils / Risk factors / Type 2 diabetes