Inhibitor of apoptosis proteins (laps) limit Ripk1 mediated skin inflammation
- Author(s)
- Anderton, H; Rickard, JA; VARIGOS, GA; Lalaoui, N; Silke, J;
- Journal Title
- J Invest Dermatol
- Publication Type
- Journal Article in press
- Abstract
- Inhibitor of Apoptosis Proteins (IAPs) are critical regulators of cell death and survival pathways. Mice lacking cellular IAP (cIAP) 1 and either cIAP2 or X-linked IAP (XIAP) die in utero, and myeloid lineage-specific deletion of all IAPs causes sterile inflammation, but their role in the skin is unknown. We generated epidermal-specific IAPs deficient mice and found that combined genetic deletion of cIAP1 in keratinocytes and ubiquitous cIAP2 deletion (cIap1EKO/EKO.cIap2-/-) caused profound skin inflammation and keratinocyte death, lethal by post-partum day 10. To investigate their role in skin homeostasis, we injected an IAP antagonist compound subcutaneously into wild-type and knockout mice. This induced a Toxic Epidermal Necrolysis like local inflammation, which mirrored the phenotype seen in cIap1EKO/EKO.cIap2-/- mice. Loss of one Ripk1 allele limited lesion formation, and significantly extended the lifespan of cIap1EKO/EKO.cIap2-/- mice. cIAPs activities are important for recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to signalling complexes, and loss of LUBAC component, SHARPIN, induces dermatitis in mice. Consistent with this relationship between cIAPs and LUBAC, Ripk1 heterozygosity also protected against development of dermatitis in Sharpin deficient mice. This work therefore refines our molecular understanding of inflammatory signalling in the skin and defines potential targets for treating skin inflammation.
- Publisher
- Elsevier
- Research Division(s)
- Cell Signalling And Cell Death
- PubMed ID
- 28647349
- Publisher's Version
- https://doi.org/10.1016/j.jid.2017.05.031
- NHMRC Grants
- NHMRC/1025594, NHMRC/1046984, NHMRC/1081221, NHMRC/1093637,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-07-26 12:48:09
Last Modified: 2017-07-26 02:37:00