Caspase-8 deficiency in mouse embryos triggers chronic RIPK1-dependent activation of inflammatory genes, independently of RIPK3

Tae-Bong Kang,Seung-Hoon Yang,Andrew Kovalenko,David Wallach,Ju-Seong Jeong

doi:10.1038/s41418-018-0104-9

Abstract

Deletion of the Casp8 gene in epithelial tissues of mice results in severe inflammatory pathologies. Its ubiquitous deletion, or its specific deletion in endothelial cells, results in intrauterine death associated with capillary damage. These pathologies are all preventable by co-deletion of Casp8 and the genes encoding either the RIPK1 or the RIPK3 protein kinase. Since activation of RIPK3 in Caspase-8-deficient cells can trigger necroptotic cell death, and since RIPK1 can activate RIPK3, it is widely assumed that the inflammatory states resulting from Caspase-8 deficiency occur as a consequence of RIPK3-induced necroptosis. Here, we report that although on a Ripk3-null background Casp8 deletion in mice does not result in outright pathological changes, it triggers enhanced expression of a variety of inflammatory genes in utero, which gradually subsides after birth. Deletion of Ripk1, or even of only one of its two alleles, obliterates this activation. Resembling the embryonic pathology observed in RIPK3-expressing cells, the activation of inflammatory genes observed on a Ripk3-null background seems to be initiated in endothelial cells. Analysis of endothelial cells isolated from livers of Caspase-8-deficient embryos revealed neither an increase in the amount of RIPK1 in these cells after Casp8 deletion, nor triggering of RIPK1 phosphorylation. These findings indicate that the triggering of inflammation by Casp8 deletion in mice occurs, in part, independently of necroptosis or other functions of RIPK3, and rather reflects enhanced RIPK1-dependent signaling for activation of inflammatory genes.

Highlights

Caspase-8 is unique among members of the caspase cysteine protease family with regard to the far-reachingEdited by A
By employing the Nanostring technique to profile the genes expressed in embryonic livers of those Casp8−/−Ripk3−/− embryos, using a panel of 547 mouse genes known to contribute to the immune response, we found that besides the increase in interleukin Il1b, Caspase-8 deficiency resulted in upregulation of many other inflammatory genes (Fig. 1a)
The prevailing conception of the various pathological changes resulting from Caspase-8 deficiency is that they are all mediated through a common mechanism in which sequential activation of RIPK1 and RIPK3 results in phosphorylation of the Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase. The latter mediates necroptotic death of Caspase-8-deficient cells, and DAMPs released by the dying cells trigger the inflammatory changes associated with these various pathologies

Summary

Introduction

Caspase-8 is unique among members of the caspase cysteine protease family with regard to the far-reachingEdited by A. Caspase-8 is unique among members of the caspase cysteine protease family with regard to the far-reaching. These authors contributed : Tae-Bong Kang, Ju-Seong Jeong. The finding that certain pathogens have evolved mechanisms to block the function of caspases, including that of Caspase-8, has drawn considerable attention to mechanisms accounting for the inflammatory states dictated by Casp deletion, and the possible real-life corollaries of these experimental pathologies [10]. Assessment of the consequences of Caspase-8 deficiency in cultured cells revealed that these cells, while resistant to apoptotic-death induction by receptors of the TNF family, display

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Conclusion