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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
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Evaluation of Caspase Activation to Assess Innate Immune Cell Death

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Protective roles for caspase-8 and cFLIP in adult homeostasis

Ricardo Weinlich1, Andrew Oberst, Christopher P Dillon

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Cell Reports
|October 8, 2013
PubMed

Insights

Caspase-8 deficiency in adult mice causes tissue death and inflammation, leading to mortality. This lethal phenotype is prevented by inhibiting RIPK3, highlighting caspase-8

Area of Science:

  • Molecular and Cellular Biology
  • Immunology
  • Developmental Biology

Background:

  • Caspase-8 and cFLIP deficiencies cause embryonic lethality.
  • Caspase-8 antagonizes RIPK3's lethal effects during development.

Purpose of the Study:

  • To investigate the role of caspase-8 in adult tissue homeostasis.
  • To determine the interplay between caspase-8, RIPK3, and cFLIP in adult tissues.

Main Methods:

  • Acute deletion of caspase-8 in adult mouse gut and skin.
  • Genetic ablation of RIPK3 in caspase-8 deficient mice.
  • Tumor Necrosis Factor (TNF) neutralization.

Main Results:

  • Acute caspase-8 deletion in adult mice induces enterocyte and keratinocyte death, tissue disruption, and inflammation.
  • RIPK3 ablation rescues these phenotypes.
  • Acute cFLIP loss in skin causes a similar phenotype, not rescued by RIPK3 ablation.
  • TNF neutralization protects against both caspase-8 and cFLIP loss.

Conclusions:

  • Caspase-8 suppresses RIPK3-induced death in adult homeostasis, similar to its developmental role.
  • RIPK3-dependent inflammation is not essential for the skin phenotype caused by caspase-8 loss.
  • TNF signaling is critical in caspase-8 and cFLIP-mediated cell death pathways.

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