美国基因泰克公司Vishva M. Dixit等研究人员合作发现，用NINJ1抗体抑制膜的破裂可限制组织的损伤。相关论文于2023年5月17日在线发表在《自然》杂志上。

研究人员报道了一种抗NINJ1的单克隆抗体，专门针对小鼠NINJ1，它能阻断NINJ1的低聚物，并防止质膜破裂（PMR）。通过电子显微镜，这种抗体阻止了NINJ1形成寡聚丝。在小鼠中，抑制NINJ1或Ninj1缺失可改善TNF加D-半乳糖胺、Concanavalin 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，血清中的乳酸脱氢酶（LDH）、肝脏酶丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）以及损伤相关分子模式（DAMP）白细胞介素18（IL-18）和HMGB1的水平都有所下降。此外，在肝脏IRI模型中，随之而来的是中性粒细胞浸润的减少。这些数据表明，NINJ1在由异常肝细胞死亡驱动的疾病中介导PMR和炎症。

据悉，经历焦亡或凋亡的垂死细胞的PMR需要细胞表面蛋白NINJ11。PMR释放出促炎症的细胞质分子，统称为DAMP，进而激活免疫细胞。因此，抑制NINJ1和PMR可能会限制与细胞过度死亡有关的炎症。

附：英文原文

Title: Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury

Author: Kayagaki, Nobuhiko, Stowe, Irma B., Alegre, Kamela, Deshpande, Ishan, Wu, Shuang, Lin, Zhonghua, Kornfeld, Opher S., Lee, Bettina L., Zhang, Juan, Liu, John, Suto, Eric, Lee, Wyne P., Schneider, Kellen, Lin, WeiYu, Seshasayee, Dhaya, Bhangale, Tushar, Chalouni, Cecile, Johnson, Matthew C., Joshi, Prajakta, Mossemann, Jan, Zhao, Sarah, Ali, Danish, Goldenberg, Neil M., Sayed, Blayne A., Steinberg, Benjamin E., Newton, Kim, Webster, Joshua D., Kelly, Ryan L., Dixit, Vishva M.

Issue&Volume: 2023-05-17

Abstract: 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.

DOI: 10.1038/s41586-023-06191-5

Source: https://www.nature.com/articles/s41586-023-06191-5