Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Biochemistry | Endocrine System Diseases | Endocrinology, Diabetes, and Metabolism | Enzymes and Coenzymes | Immune System Diseases | Medicinal-Pharmaceutical Chemistry | Nutritional and Metabolic Diseases | Therapeutics
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.
Type 1 diabetes, NOD mice, Neutrophils, Prevention, T Cells, Protein citrullination
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© 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
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
Sodré FM, 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. (2020). Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice. Thompson Lab Publications. https://doi.org/10.2337/db20-0421. Retrieved from https://escholarship.umassmed.edu/thompson/118
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