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Updated: May 5, 2026
Murine Model of Intestinal Ischemia-reperfusion Injury
Published on: May 11, 2016
Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury
Nobuhiko Kayagaki1, Irma B Stowe2, Kamela Alegre2
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. kayagaki@gene.com.
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.
Insights
Researchers developed an anti-NINJ1 antibody to block plasma membrane rupture (PMR) in dying cells. This inhibition reduces inflammation and damage-associated molecular patterns (DAMPs), offering a potential therapeutic strategy for inflammatory diseases.
Area of Science:
- Cell Biology
- Immunology
- Biochemistry
Background:
- Plasma membrane rupture (PMR) is a key event in cell death pathways like pyroptosis and apoptosis.
- NINJ1 is a cell-surface protein essential for mediating PMR.
- PMR releases damage-associated molecular patterns (DAMPs), triggering inflammation.
Purpose of the Study:
- To develop a therapeutic agent targeting NINJ1 to inhibit PMR.
- To investigate the role of NINJ1 in mediating inflammation associated with excessive cell death.
- To evaluate the efficacy of anti-NINJ1 antibody in preclinical models.
Main Methods:
- Development of a monoclonal antibody against mouse NINJ1.
- Electron microscopy to visualize NINJ1 oligomerization.
- In vivo studies using mouse models of liver injury (TNF/D-galactosamine, concanavalin A, Jo2, ischemia-reperfusion).
- Measurement of serum biomarkers (LDH, ALT, AST) and DAMPs (IL-18, HMGB1).
Main Results:
- The anti-NINJ1 antibody specifically targets mouse NINJ1 and prevents its oligomerization and filament formation.
- Inhibition of NINJ1 or genetic deficiency ameliorated hepatocellular PMR in various injury models.
- Reduced serum levels of liver enzymes and DAMPs were observed.
- Decreased neutrophil infiltration was noted in the ischemia-reperfusion injury model.
Conclusions:
- NINJ1 is a critical mediator of plasma membrane rupture and subsequent inflammation in hepatocellular death.
- Targeting NINJ1 with monoclonal antibodies represents a potential therapeutic approach to mitigate inflammation in diseases characterized by excessive cell death.
