Journal
JOURNAL OF IMMUNOLOGY
Volume 203, Issue 4, Pages 795-800Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800720
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Funding
- German Research Foundation [DFG BO 4325/1-1]
- National Institutes of Health [R35 GM118112]
- Hannover Medical School Intramural Grant HiLF
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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-1 beta release in macrophages. Genetic deficiency of either PAD2 or PAD4 alone in murine macrophages does not impair IL-1 beta 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-1 beta release, a finding of importance for autoimmune diseases and inflammation.
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