Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.

Summary

This mechanistic study shows that NINJ1-mediated plasma membrane rupture is a key step linking inflammasome activation to the release of procoagulant TF-positive microvesicles, driving coagulopathy and inflammation. Genetic haploinsufficiency or glycine inhibition of NINJ1 reduced microvesicle and cytokine release and partially protected against flagellin-induced coagulopathy and death.

Key Findings

• NINJ1 promotes release of TF-positive procoagulant microvesicles during pyroptosis.
• NINJ1 haploinsufficiency or glycine inhibition reduces microvesicle and cytokine release.
• Inhibition of NINJ1-dependent membrane rupture partially protects against flagellin-induced coagulopathy and lethality.

Clinical Implications

While preclinical, targeting NINJ1 or downstream membrane rupture may complement anticoagulation and anti-inflammatory strategies in sepsis/COVID coagulopathy. Development of selective NINJ1 inhibitors and biomarker-guided trials are warranted.

Limitations

• Preclinical mouse models; human validation is lacking.
• Glycine is a non-specific inhibitor; selective NINJ1 inhibitors were not tested.

Future Directions

Develop selective NINJ1 inhibitors; validate NINJ1/PMR biomarkers in human sepsis; test efficacy in diverse infectious models and coagulopathy phenotypes.