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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.
Nature
|May 17, 2023
Summary
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.
