Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice

Diabetes. 2021 Feb;70(2):516-528. doi: 10.2337/db20-0421. Epub 2020 Nov 17.

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 glucose-regulated protein 78, and reduced spontaneous neutrophil extracellular trap formation 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 interferon-γ-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / prevention & control
  • Extracellular Traps / drug effects
  • Extracellular Traps / metabolism
  • Insulin / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Ornithine / analogs & derivatives*
  • Ornithine / pharmacology
  • Pancreas / drug effects*
  • Pancreas / metabolism
  • Protein-Arginine Deiminases / antagonists & inhibitors*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Cytokines
  • Insulin
  • N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
  • Ornithine
  • Protein-Arginine Deiminases

Associated data

  • figshare/10.2337/figshare.13221704