Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Department of Structural Biology, Genentech, South San Francisco, CA, USA.
Nature. 2023 Jun;618(7967):1072-1077. doi: 10.1038/s41586-023-06191-5. Epub 2023 May 17.
Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.
细胞发生细胞焦亡或细胞凋亡时会发生质膜破裂（PMR），这需要细胞表面蛋白 NINJ1。PMR 会释放促炎细胞质分子，这些分子统称为损伤相关分子模式（DAMPs），可激活免疫细胞。因此，抑制 NINJ1 和 PMR 可能会限制与过度细胞死亡相关的炎症。在这里，我们描述了一种抗 NINJ1 单克隆抗体，它特异性靶向小鼠 NINJ1 并阻断 NINJ1 的寡聚化，从而阻止 PMR。电子显微镜研究表明，这种抗体可防止 NINJ1 形成寡聚纤维。在小鼠中，抑制 NINJ1 或 Ninj1 缺乏可改善 TNF 加 D-半乳糖胺、伴刀豆球蛋白 A、Jo2 抗 Fas 激动剂抗体或缺血再灌注损伤诱导的肝细胞 PMR。因此，血清中乳酸脱氢酶、肝酶丙氨酸氨基转移酶和天冬氨酸氨基转移酶以及 DAMPs 白细胞介素 18 和高迁移率族蛋白 B1 的水平降低。此外，在肝脏缺血再灌注损伤模型中，中性粒细胞浸润也随之减少。这些数据表明，NINJ1 介导了由异常肝细胞死亡驱动的疾病中的 PMR 和炎症。
