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J Immunol. 2019 Jul 10. pii: ji1800720. doi: 10.4049/jimmunol.1800720. [Epub ahead of print]

Cutting Edge: Protein Arginine Deiminase 2 and 4 Regulate NLRP3 Inflammasome-Dependent IL-1β Maturation and ASC Speck Formation in Macrophages.

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Section of Rheumatology, Department of Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany.
Department of Biomedical Sciences, Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605.
Department of Dermatology, University of Heidelberg, 69120 Heidelberg, Germany.
Department of Clinical Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany; and.
Department of Medicine A, University Medicine Greifswald, 1745 Greifswald, Germany.
Section of Rheumatology, Department of Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany;


Protein arginine deiminase (PAD) enzymes catalyze the conversion of protein-bound arginine into citrulline, an irreversible posttranslational modification with loss of a positive charge that can influence protein-protein interactions and protein structure. Protein arginine deiminase activity depends on high intracellular calcium concentrations occurring in dying cells. In this study, we demonstrate that protein citrullination is common during pyroptotic cell death in macrophages and that inhibition of PAD enzyme activity by Cl-amidine, a pan-PAD inhibitor, blocks NLRP3 inflammasome assembly and proinflammatory IL-1β release in macrophages. Genetic deficiency of either PAD2 or PAD4 alone in murine macrophages does not impair IL-1β release; however, pharmacological inhibition or small interfering RNA knockdown of PAD2 within PAD4-/- macrophages does. Our results suggest that PAD2 and 4 activity in macrophages is required for optimal inflammasome assembly and IL-1β release, a finding of importance for autoimmune diseases and inflammation.


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