Ninj1, or nerve injury-induced protein 1, is a cell-surface protein with two transmembrane regions. It plays an essential role in plasma membrane rupture (PMR) during lytic cell death, a process that releases damage-associated molecular patterns (DAMPs) and propagates the inflammatory response [1]. PMR is involved in pyroptotic, necrotic, and apoptotic cell death pathways, as well as in anti-bacterial host defence [1].

In Ninj1-/-macrophages, PMR was impaired in response to diverse inducers of cell death, and they could not release intracellular proteins like HMGB1 and LDH, despite still dying but with a ballooned morphology [1]. Ninj1-/-mice were more susceptible to Citrobacter rodentium infection, indicating a role of Ninj1-mediated PMR in anti-bacterial host defence [1]. In the context of liver ischemia-reperfusion injury, Ninj1 deficiency in Kupffer cells protected mice against injury, especially in neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis [3]. Also, an anti-Ninj1 monoclonal antibody that blocks Ninj1 oligomerization and prevents PMR was shown to ameliorate hepatocellular PMR in mice, reducing serum levels of lactate dehydrogenase, liver enzymes, and DAMPs [2].

In conclusion, Ninj1 is a key mediator of PMR during lytic cell death, with implications in inflammation and host defence. Gene-knockout mouse models, such as Ninj1-/-mice, have been crucial in revealing its role in anti-bacterial host defence and in diseases like liver ischemia-reperfusion injury, highlighting its potential as a therapeutic target for conditions associated with excessive cell death and inflammation.

References:

1. Kayagaki, Nobuhiko, Kornfeld, Opher S, Lee, Bettina L, Bertram, Edward M, Dixit, Vishva M. 2021. NINJ1 mediates plasma membrane rupture during lytic cell death. In Nature, 591, 131-136. doi:10.1038/s41586-021-03218-7. https://pubmed.ncbi.nlm.nih.gov/33472215/

2. Kayagaki, Nobuhiko, Stowe, Irma B, Alegre, Kamela, Kelly, Ryan L, Dixit, Vishva M. 2023. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury. In Nature, 618, 1072-1077. doi:10.1038/s41586-023-06191-5. https://pubmed.ncbi.nlm.nih.gov/37196676/

3. Hu, Yuanchang, Zhan, Feng, Wang, Yong, Wang, Xun, Zhou, Shun. 2023. The Ninj1/Dusp1 Axis Contributes to Liver Ischemia Reperfusion Injury by Regulating Macrophage Activation and Neutrophil Infiltration. In Cellular and molecular gastroenterology and hepatology, 15, 1071-1084. doi:10.1016/j.jcmgh.2023.01.008. https://pubmed.ncbi.nlm.nih.gov/36731792/