Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice
AuthorsSodré, Fernanda M. C.
Cook, Dana P.
Thompson, Paul R.
UMass Chan AffiliationsThompson Lab
Department of Biochemistry and Molecular Pharmacology
Document TypeAccepted Manuscript
KeywordsType 1 diabetes
Endocrine System Diseases
Endocrinology, Diabetes, and Metabolism
Enzymes and Coenzymes
Immune System Diseases
Nutritional and Metabolic Diseases
MetadataShow full item record
AbstractProtein 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.
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