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Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury

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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.

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Correspondence to Nobuhiko Kayagaki or Vishva M. Dixit.

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Supplementary Table 1

A list of all antibodies used in this study.

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Kayagaki, N., Stowe, I.B., Alegre, K. et al. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury. Nature (2023).

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