TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• SHARPIN is crucial for immune signaling, regulating transcriptional activity and preventing cell death upon tumor necrosis factor (TNF) exposure.
• A mutation in SHARPIN (cpdm) in mice leads to TNF-dependent multi-organ inflammation, including dermatitis and liver inflammation.

Purpose of the Study:

• To investigate the mechanisms underlying SHARPIN-mediated regulation of TNF-induced inflammation.
• To determine the roles of TNFR1, CASP8, RIPK3, and MLKL in the inflammatory phenotype associated with SHARPIN deficiency.

Main Methods:

• Analysis of Sharpin cpdm mutant mice with targeted deficiencies in TNF receptor 1 (TNFR1), TNFR2, IL1R1, CASP8, RIPK3, and MLKL.
• Assessment of inflammatory phenotypes, including dermatitis, liver inflammation, splenomegaly, and Peyer's patch integrity.

Main Results:

• TNFR1 deficiency, but not TNFR2 or IL1R1 deficiency, significantly suppressed the inflammatory phenotype.
• While CASP8 and BID loss had limited effects, RIPK3 or MLKL deficiency partially ameliorated the inflammation.
• Combined RIPK3 deletion and CASP8 heterozygosity nearly abolished the phenotype, but triple deficiency of SHARPIN, RIPK3, and CASP8 resulted in perinatal lethality.

Conclusions:

• The study elucidates the critical role of TNFR1 signaling in SHARPIN-deficient inflammation.
• RIPK3 and CASP8 are key mediators, with their combined inhibition largely rescuing the phenotype.
• The unexpected perinatal lethality in triple-deficient mice highlights the essential developmental function of SHARPIN beyond its role in immune regulation.