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Inhibitor of Apoptosis Proteins (IAPs) Limit RIPK1-Mediated Skin Inflammation

Holly Anderton1, James A Rickard1, George A Varigos2

  • 1The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.

The Journal of Investigative Dermatology
|June 26, 2017
PubMed

Insights

Inhibitor of apoptosis proteins (IAPs) are crucial for skin health. Genetic deletion or antagonism of IAPs in mice causes lethal skin inflammation, highlighting their importance in preventing cell death and maintaining skin homeostasis.

Area of Science:

  • Molecular Biology
  • Immunology
  • Dermatology

Background:

  • Inhibitor of apoptosis proteins (IAPs) regulate cell death and survival.
  • The role of IAPs in skin homeostasis and inflammation is largely unknown.
  • Previous studies show IAP deficiency causes embryonic lethality or sterile inflammation in other tissues.

Purpose of the Study:

  • To investigate the role of IAPs in epidermal homeostasis and skin inflammation.
  • To determine the consequences of IAP deficiency in keratinocytes.
  • To explore therapeutic targets for skin inflammation.

Main Methods:

  • Generated epidermal-specific IAP-deficient mice (cIAP1 EKO).
  • Utilized combined genetic deletion of cIAP1 and cIAP2.
  • Administered IAP antagonist compound to wild-type and knockout mice.
  • Investigated the role of Ripk1 and LUBAC signaling pathways.

Main Results:

  • Combined deletion of cIAP1 and cIAP2 in epidermis caused lethal skin inflammation and keratinocyte death.
  • IAP antagonism induced toxic epidermal necrolysis-like inflammation.
  • Loss of one Ripk1 allele ameliorated inflammation and extended lifespan.
  • Ripk1 heterozygosity protected against dermatitis in Sharpin-deficient mice.

Conclusions:

  • cIAP1 and cIAP2 are essential for preventing skin inflammation and keratinocyte death.
  • IAP antagonism can trigger severe skin inflammation.
  • Ripk1 and LUBAC signaling pathways are critical in IAP-mediated skin homeostasis and inflammation.
  • These findings identify potential therapeutic targets for treating skin inflammatory diseases.

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