UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2020-11-17

Document Type

Article Postprint

Disciplines

Biochemistry | Endocrine System Diseases | Endocrinology, Diabetes, and Metabolism | Enzymes and Coenzymes | Immune System Diseases | Medicinal-Pharmaceutical Chemistry | Nutritional and Metabolic Diseases | Therapeutics

Abstract

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of IFNγ-producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes.

Keywords

Type 1 diabetes, NOD mice, Neutrophils, Prevention, T Cells, Protein citrullination

Rights and Permissions

© 2020 by the American Diabetes Association https://www.diabetesjournals.org/content/license. 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. Accepted manuscript posted as allowed by the publisher's self-archiving policy at https://www.diabetesjournals.org/content/ada-policies-and-procedures-peer-reviewed-publications?survey=1#acceptedmanuscripts.

DOI of Published Version

10.2337/db20-0421

Source

Sodré FMC, Bissenova S, Bruggeman Y, Tilvawala R, Cook DP, Berthault C, Mondal S, Callebaut A, You S, Scharfmann R, Mallone R, Thompson PR, Mathieu C, Buitinga M, Overbergh L. Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice. Diabetes. 2020 Nov 17:db200421. doi: 10.2337/db20-0421. Epub ahead of print. PMID: 33203696. Link to article on publisher's site

Journal/Book/Conference Title

Diabetes

Related Resources

Article in PubMed

PubMed ID

33203696

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