Expression and Regulation of Chemokines in Murine and Human Type 1 Diabetes

Author:

Sarkar Suparna A.1,Lee Catherine E.1,Victorino Francisco12,Nguyen Tom T.1,Walters Jay A.1,Burrack Adam12,Eberlein Jens1,Hildemann Steven K.3,Homann Dirk124

Affiliation:

1. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado

2. Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado

3. Innere Medizin III, Unversitätsklinik Freiburg, Freiburg, Germany

4. Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado

Abstract

More than one-half of the ~50 human chemokines have been associated with or implicated in the pathogenesis of type 1 diabetes, yet their actual expression patterns in the islet environment of type 1 diabetic patients remain, at present, poorly defined. Here, we have integrated a human islet culture system, murine models of virus-induced and spontaneous type 1 diabetes, and the histopathological examination of pancreata from diabetic organ donors with the goal of providing a foundation for the informed selection of potential therapeutic targets within the chemokine/receptor family. Chemokine (C-C motif) ligand (CCL) 5 (CCL5), CCL8, CCL22, chemokine (C-X-C motif) ligand (CXCL) 9 (CXCL9), CXCL10, and chemokine (C-X3-C motif) ligand (CX3CL) 1 (CX3CL1) were the major chemokines transcribed (in an inducible nitric oxide synthase–dependent but not nuclear factor-κB–dependent fashion) and translated by human islet cells in response to in vitro inflammatory stimuli. CXCL10 was identified as the dominant chemokine expressed in vivo in the islet environment of prediabetic animals and type 1 diabetic patients, whereas CCL5, CCL8, CXCL9, and CX3CL1 proteins were present at lower levels in the islets of both species. Of importance, additional expression of the same chemokines in human acinar tissues emphasizes an underappreciated involvement of the exocrine pancreas in the natural course of type 1 diabetes that will require consideration for additional type 1 diabetes pathogenesis and immune intervention studies.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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