TNFR1-dependent cell death drives infammation in Sharpin-defcient mice

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ infammation, characterized by dermatitis, liver infammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the infammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, defciency suppresses the phenotype (and it does so more effciently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress infammation, although Casp8 heterozygosity signifcantly delayed dermatitis. Ripk3 or Mlkl defciency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple defciency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.