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Diabetologia. 2018 Nov;61(11):2333-2343. doi: 10.1007/s00125-018-4705-0. Epub 2018 Aug 9.

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

Author information

1
Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, Yale University, 300 Cedar Street, New Haven, CT, 06520, USA.
2
Jounce Therapeutics Inc., Cambridge, MA, USA.
3
Department of Rheumatology, PLA General Hospital, Beijing, People's Republic of China.
4
Department of Bioinformatics, Yale School of Public Health, Yale University, New Haven, CT, USA.
5
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK. WongFS@Cardiff.ac.uk.
6
Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, Yale University, 300 Cedar Street, New Haven, CT, 06520, USA. li.wen@yale.edu.

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.

KEYWORDS:

CD140a; Diabetes; Islet beta cell; PDGFRα; TLR9

PMID:
30094467
PMCID:
PMC6182661
DOI:
10.1007/s00125-018-4705-0
[Indexed for MEDLINE]
Free PMC Article

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