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Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes

Liu, Mengju, Peng, Jian, Tai, Ningwen, Pearson, James A., Hu, Changyun, Guo, Junhua, Hou, Lin, Zhao, Hongyu, Wong, F. Susan and Wen, Li 2018. Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes. Diabetologia 61 (11) , pp. 2333-2343. 10.1007/s00125-018-4705-0

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Abstract

Aims/hypothesis Innate immune effectors interact with the environment to contribute to the pathogenesis of the autoimmune disease, type 1 diabetes. Although recent studies have suggested that innate immune Toll-like receptors (TLRs) are involved in tissue development, little is known about the role of TLRs in tissue development, compared with autoimmunity. We aimed to fill the knowledge gap by investigating the role of TLR9 in the development and function of islet beta cells in type 1 diabetes, using NOD mice. Methods We generated Tlr9−/− NOD mice and examined them for type 1 diabetes development and beta cell function, including insulin secretion and glucose tolerance. We assessed islet and beta cell number and characterised CD140a expression on beta cells by flow cytometry. We also tested beta cell function in Tlr9−/− C57BL/6 mice. Finally, we used TLR9 antagonists to block TLR9 signalling in wild-type NOD mice to verify the role of TLR9 in beta cell development and function. Results TLR9 deficiency promoted pancreatic islet development and beta cell differentiation, leading to enhanced glucose tolerance, improved insulin sensitivity and enhanced first-phase insulin secretory response. This was, in part, mediated by upregulation of CD140a (also known as platelet-derived growth factor receptor-α [PDGFRα]). In the absence of TLR9, induced by either genetic targeting or treatment with TLR9 antagonists, which had similar effects on ontogenesis and function of beta cells, NOD mice were protected from diabetes. Conclusions/interpretation Our study links TLR9 and the CD140a pathway in regulating islet beta cell development and function and indicates a potential therapeutic target for diabetes prevention and/or treatment.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Springer Verlag (Germany)
ISSN: 0012-186X
Date of First Compliant Deposit: 29 August 2018
Date of Acceptance: 2 July 2018
Last Modified: 04 Oct 2018 13:50
URI: http://orca.cf.ac.uk/id/eprint/114457

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