Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes.

This is the author accepted manuscript. The final version is freely available from Nature Publishing Group via the DOI in this record.Chronic inflammation plays a key role in both type 1 and type 2 diabetes. Cytokine and chemokine production within the islets in a diabetic milieu results in β-cell failure and diabetes progression. Identification of targets, which both prevent macrophage activation and infiltration into islets and restore β-cell functionality is essential for effective diabetes therapy. We report that certain Sialic-acid-binding immunoglobulin-like-lectins (siglecs) are expressed in human pancreatic islets in a cell-type specific manner. Siglec-7 was expressed on β-cells and down-regulated in type 1 and type 2 diabetes and in infiltrating activated immune cells. Over-expression of Siglec-7 in diabetic islets reduced cytokines, prevented β-cell dysfunction and apoptosis and reduced recruiting of migrating monocytes. Our data suggest that restoration of human Siglec-7 expression may be a novel therapeutic strategy targeted to both inhibition of immune activation and preservation of β-cell function and survival.This work was supported by the European Research Council (ERC), the JDRF, the Northcott Devon Medical Foundation and Diabetes UK, NIH grant P01HL107150. We thank Julie Kerr-Conte and Francois Pattou, European Genomic Institute for Diabetes, INSERM UMR 1190, Lille, France for the high quality human islet isolations. We would like to thank Prof. Dr. Paul Crocker, Dundee, for fruitful discussion and advice and providing us the sheep anti-siglec antibodies and the CHO-Siglec-7 cell line, Katrischa Hennekens for excellent technical assistance; Hanna Kirchhoff, Katharina Zyromski, Payal Shah, Wei He and Anke Meyer for help with the analyses, Anna-Leena Krämer and Andreas Dotzauer (all Uni Bremen) for their help with the FACS analysis and Melanie Braun and Lutz Schmidt (Asklepios Klinik Hamburg) for providing the human buffy coats. Human islets were provided through the JDRF award 31-2008-416 (ECIT Islet for Basic Research program) and from the Integrated Islet Distribution Program (IIDP): Human Islets for Research funded through a contract from the National Institute of Diabetes and Kidney and Digestive Diseases (NIDDK) and the JDRF. Human pancreatic sections were provided from the National Disease Research Interchange (NDRI), supported by the NIH