Immunity
Volume 49, Issue 1, 17 July 2018, Pages 42-55.e6
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Article
Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock

https://doi.org/10.1016/j.immuni.2018.06.011Get rights and content
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Highlights

  • Pro-apoptotic Casp8 is essential for lethal LPS shock and E. coli sepsis

  • Initiation of cytokine production proceeds independent of Casp8 and Casp11

  • TNF and type 1 IFN drive Casp8 and Casp11 collaboration in target tissues

  • Combined pro-apoptotic and pro-pyroptotic signaling executes LPS shock

Summary

The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-β-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.

Keywords

Caspase
RIP kinase
extrinsic apoptosis
programmed necrosis
pyroptosis
TNF
interferon
ileum
endotoxic shock

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