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.
J Immunol. 2019 Aug 15;203(4):795-800. doi: 10.4049/jimmunol.1800720. Epub 2019 Jul 10.
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.
蛋白精氨酸脱亚氨酶（PAD）酶催化将蛋白质结合的精氨酸转化为瓜氨酸，这是一种不可逆的翻译后修饰，失去了正电荷，会影响蛋白质-蛋白质相互作用和蛋白质结构。蛋白精氨酸脱亚氨酶活性依赖于细胞死亡时细胞内的高钙离子浓度。在这项研究中，我们证明了在巨噬细胞的细胞焦亡过程中，蛋白质瓜氨酸化很常见，而泛 PAD 抑制剂 Cl-amidine 抑制 PAD 酶活性可阻断 NLRP3 炎性体的组装和巨噬细胞中促炎的 IL-1β释放。在鼠巨噬细胞中单独缺乏 PAD2 或 PAD4 并不影响 IL-1β的释放；然而，在 PAD4 巨噬细胞中使用 PAD2 的药理学抑制剂或小干扰 RNA 敲低会抑制其释放。我们的结果表明，巨噬细胞中 PAD2 和 PAD4 的活性对于炎性体的最佳组装和 IL-1β的释放是必需的，这一发现对自身免疫性疾病和炎症具有重要意义。
