Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1¹. PMR releases proinflammatory 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, specifically targeting murine NINJ1, that blocks oligomerization of NINJ1 and prevents PMR. By electron microscopy, this antibody prevented 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 ischemia-reperfusion injury (IRI). Accordingly, serum levels of lactate dehydrogenase (LDH), liver enzymes alanine aminotransaminase (ALT) and aspartate aminotransferase (AST), and DAMPs interleukin 18 (IL-18) and HMGB1 were reduced. Moreover, in the liver IRI 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.

正在经历焦亡或凋亡的垂死细胞的质膜破裂 (PMR) 需要细胞表面蛋白 NINJ1 ¹。PMR 释放促炎细胞质分子，统称为损伤相关分子模式 (DAMP)，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，专门针对小鼠 NINJ1，可阻断 NINJ1 寡聚化并预防 PMR。通过电子显微镜观察，该抗体阻止 NINJ1 形成寡聚丝。在小鼠中，抑制 NINJ1 或Ninj1缺乏可改善 TNF 加 D-半乳糖胺、刀豆球蛋白 A、Jo2 抗 Fas 激动剂抗体或缺血再灌注损伤 (IRI) 诱导的肝细胞 PMR。因此，乳酸脱氢酶（LDH）、肝酶丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）以及DAMPs白细胞介素18（IL-18）和HMGB1的血清水平降低。此外，在肝脏 IRI 模型中，中性粒细胞浸润随之减少。这些数据表明，NINJ1 在异常肝细胞死亡驱动的疾病中介导 PMR 和炎症。