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

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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