Increased Expression of CCL2 in Insulin-Producing Cells of Transgenic Mice Promotes Mobilization of Myeloid Cells From the Bone Marrow, Marked Insulitis, and Diabetes

  1. Andrea P. Martin1,
  2. Sara Rankin2,
  3. Simon Pitchford2,
  4. Israel F. Charo34,
  5. Glaucia C. Furtado1 and
  6. Sergio A. Lira1
  1. 1Immunology Institute, Mount Sinai School of Medicine, New York, New York
  2. 2Leukocyte Biology Section, NHLI Division, Faculty of Medicine, Imperial College, South Kensington Campus, London, U.K
  3. 3Gladstone Institute of Cardiovascular Disease, Department of Medicine, University of California, San Francisco, California
  4. 4Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco, California
  1. Corresponding author: Sergio A. Lira, sergio.lira{at}mssm.edu, or Glaucia C. Furtado, glaucia.furtado{at}mssm.edu

Abstract

OBJECTIVE—To define the mechanisms underlying the accumulation of monocytes/macrophages in the islets of Langerhans.

RESEARCH DESIGN AND METHODS—We tested the hypothesis that macrophage accumulation into the islets is caused by overexpression of the chemokine CCL2. To test this hypothesis, we generated transgenic mice and evaluated the cellular composition of the islets by immunohistochemistry and flow cytometry. We determined serum levels of CCL2 by enzyme-linked immunosorbent assay, determined numbers of circulating monocytes, and tested whether CCL2 could mobilize monocytes from the bone marrow directly. We examined development of diabetes over time and tested whether CCL2 effects could be eliminated by deletion of its receptor, CCR2.

RESULTS—Expression of CCL2 by β-cells was associated with increased numbers of monocytes in circulation and accumulation of macrophages in the islets of transgenic mice. These changes were promoted by combined actions of CCL2 at the level of the bone marrow and the islets and were not seen in animals in which the CCL2 receptor (CCR2) was inactivated. Mice expressing higher levels of CCL2 in the islets developed diabetes spontaneously. The development of diabetes was correlated with the accumulation of large numbers of monocytes in the islets and did not depend on T- and B-cells. Diabetes could also be induced in normoglycemic mice expressing low levels of CCL2 by increasing the number of circulating myeloid cells.

CONCLUSIONS—These results indicate that CCL2 promotes monocyte recruitment by acting both locally and remotely and that expression of CCL2 by insulin-producing cells can lead to insulitis and islet destruction.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    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.

    See accompanying commentary, p. 2922.

    • Accepted July 1, 2008.
    • Received May 8, 2008.
| Table of Contents

This Article

  1. Diabetes vol. 57 no. 11 3025-3033
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db08-0625v1
    2. 57/11/3025 most recent