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 and Vishva M. Dixit ()
Additional contact information
Nobuhiko Kayagaki: Genentech, Department of Physiological Chemistry
Irma B. Stowe: Genentech, Department of Physiological Chemistry
Kamela Alegre: Genentech, Department of Physiological Chemistry
Ishan Deshpande: Genentech, Department of Physiological Chemistry
Shuang Wu: Genentech, Department of Antibody Engineering
Zhonghua Lin: Genentech, Department of Antibody Engineering
Opher S. Kornfeld: Genentech, Department of Physiological Chemistry
Bettina L. Lee: Genentech, Department of Physiological Chemistry
Juan Zhang: Genentech, Department of Translational Immunology
John Liu: Genentech, Department of Translational Immunology
Eric Suto: Genentech, Department of Translational Immunology
Wyne P. Lee: Genentech, Department of Translational Immunology
Kellen Schneider: Genentech, Department of Antibody Engineering
WeiYu Lin: Genentech, Department of Antibody Engineering
Dhaya Seshasayee: Genentech, Department of Antibody Engineering
Tushar Bhangale: Genentech, Department of Human Genetics
Cecile Chalouni: Genentech, Department of Pathology
Matthew C. Johnson: Genentech, Department of Structural Biology
Prajakta Joshi: Genentech, Department of Biomolecular Resources
Jan Mossemann: Hospital for Sick Children, Program in Cell Biology
Sarah Zhao: Hospital for Sick Children, Program in Neuroscience and Mental Health
Danish Ali: Hospital for Sick Children, Program in Cell Biology
Neil M. Goldenberg: Hospital for Sick Children, Program in Cell Biology
Blayne A. Sayed: Hospital for Sick Children, Program in Cell Biology
Benjamin E. Steinberg: Hospital for Sick Children, Program in Neuroscience and Mental Health
Kim Newton: Genentech, Department of Physiological Chemistry
Joshua D. Webster: Genentech, Department of Pathology
Ryan L. Kelly: Genentech, Department of Antibody Engineering
Vishva M. Dixit: Genentech, Department of Physiological Chemistry

Nature, 2023, vol. 618, issue 7967, 1072-1077

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06191-5

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