Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA.
Sci Adv. 2023 Dec 22;9(51):eadj1397. doi: 10.1126/sciadv.adj1397. Epub 2023 Dec 20.
Neutrophil extracellular traps (NETs) not only counteract bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. Mitochondrial- and death receptor-mediated apoptosis promote gasdermin E (GSDME)-dependent calcium mobilization and membrane permeabilization leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit is concentrated at the promoter in bone marrow neutrophils and redistributes in a coordinated process from promoter to intergenic and intronic regions during apoptosis. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils but prolongs early apoptosis-induced cellular changes to the chromatin and cytoplasmic granules. Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end of life for neutrophils.
中性粒细胞胞外诱捕网 (NETs) 不仅能抵抗细菌和真菌病原体，还能促进血栓形成、自身免疫和无菌性炎症。由肽基精氨酸脱亚氨酶 4（PAD4）产生的瓜氨酸化组蛋白的存在与 NETosis 同义，且被认为与细胞凋亡无关。线粒体和死亡受体介导的细胞凋亡促进依赖于 gasdermin E (GSDME) 的钙动员和膜通透性增加，导致组蛋白 H3 瓜氨酸化（H3Cit）、核 DNA 挤出和细胞质小体形成。H3Cit 在骨髓中性粒细胞的启动子处浓缩，并在细胞凋亡过程中以协调的方式从启动子重新分配到基因间和内含子区域。GSDME 的缺失可防止凋亡中性粒细胞的核和质膜破裂，但会延长早期凋亡诱导的染色质和细胞质颗粒的细胞变化。凋亡信号使 PAD4 在中性粒细胞中参与，从而建立一种为 NETosis 做好准备的细胞状态，但只有在 GSDME 破坏质膜时才会发生，从而重新定义了中性粒细胞的生命终点。
