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2023

Nature. 2023 Jun;618(7967):1072-1077. doi: 10.1038/s41586-023-06191-5. Epub 2023 May 17.

Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury

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

Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. Department of Structural Biology, Genentech, South San Francisco, CA, USA. Department of Antibody Engineering, Genentech, South San Francisco, CA, USA. Department of Translational Immunology, Genentech, South San Francisco, CA, USA. Department of Human Genetics, Genentech, South San Francisco, CA, USA. Department of Pathology, Genentech, South San Francisco, CA, USA. Department of Biomolecular Resources, Genentech, South San Francisco, CA, USA. Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada. Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada. Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Ontario, Canada. Division of General Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.

Service type: Knock-in mice

Abstract

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. 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.

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