Pan-membrane pyroptosis of liver induced by gasdermin-encoding mRNAs

Area of Science:

• Cellular Biology
• Immunology
• Toxicology

Background:

• Pyroptosis, a programmed cell death pathway mediated by Gasdermin (GSDM) proteins, is well-characterized in vitro.
• The in vivo consequences and clinical relevance of pyroptosis remain largely undefined.

Purpose of the Study:

• To investigate the in vivo phenotype and clinical outcomes of pyroptosis.
• To utilize lipid-nanoparticle (LNP)-encapsulated mRNA encoding GSDMD N-terminal (GSDMD-NT) for in vivo pyroptosis induction.

Main Methods:

• Intravenous (IV) injection of LNP-mRNA encoding GSDMD-NT in mice and non-human primates.
• Administration of GSDMD inhibitor disulfiram or glucocorticoids for reversal studies.
• Advanced imaging techniques to visualize cellular and organelle damage.

Main Results:

• IV injection of GSDMD-NT mRNA induced acute liver damage, systemic inflammation, and mortality in vivo.
• Observed membrane rupture, organelle swelling, and intracellular vacuole formation.
• Pyroptosis induction and its severity varied among different GSDM members.
• Effects were reversed by disulfiram or glucocorticoids.

Conclusions:

• GSDM-mediated pyroptosis in vivo leads to significant organ damage and systemic effects.
• This study provides a model for studying pyroptotic organ injury in vivo.
• Findings support the development of GSDM-based therapeutics for pyroptosis-related diseases.