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J Allergy Clin Immunol. 2018 Mar 27. pii: S0091-6749(18)30446-9. doi: 10.1016/j.jaci.2018.02.043. [Epub ahead of print]

Blockade of TNF receptor superfamily 1 (TNFR1)-dependent and TNFR1-independent cell death is crucial for normal epidermal differentiation.

Author information

1
Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
2
Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan; Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan.
3
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
4
Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
5
Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
6
Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan.
7
Department of Pathology, Toho University School of Medicine, Tokyo, Japan.
8
Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
9
Department of Cellular Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
10
Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan; Host Defense Research Center, Toho University School of Medicine, Tokyo, Japan. Electronic address: hiroyasu.nakano@med.toho-u.ac.jp.

Abstract

BACKGROUND:

A delicate balance between cell death and keratinocyte proliferation is crucial for normal skin development. Previous studies have reported that cellular FLICE (FADD-like ICE)-inhibitory protein plays a crucial role in prevention of keratinocytes from TNF-α-dependent apoptosis and blocking of dermatitis. However, a role for cellular FLICE-inhibitory protein in TNF-α-independent cell death remains unclear.

OBJECTIVE:

We investigated contribution of TNF-α-dependent and TNF-α-independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (CflarE-KO) mice.

METHODS:

We examined the histology and expression of epidermal differentiation markers and inflammatory cytokines in the skin of CflarE-KO;Tnfrsf1a+/- and CflarE-KO;Tnfrsf1a-/- mice. Mice were treated with neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand to block TNF-α-independent cell death of CflarE-KO;Tnfrsf1a-/- mice.

RESULTS:

CflarE-KO;Tnfrsf1a-/- mice were born but experienced severe dermatitis and succumbed soon after birth. CflarE-KO;Tnfrsf1a+/- mice exhibited embryonic lethality caused by massive keratinocyte apoptosis. Although keratinocytes from CflarE-KO;Tnfrsf1a-/- mice still died of apoptosis, neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand substantially prolonged survival of CflarE-KO;Tnfrsf1a-/- mice. Expression of inflammatory cytokines, such as Il6 and Il17a was increased; conversely, expression of epidermal differentiation markers was severely downregulated in the skin of CflarE-KO;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6 and, to a lesser extent, IL-17A suppressed expression of epidermal differentiation markers.

CONCLUSION:

TNF receptor superfamily 1 (TNFR1)-dependent or TNFR1-independent apoptosis of keratinocytes promotes inflammatory cytokine production, which subsequently blocks epidermal differentiation. Thus blockade of both TNFR1-dependent and TNFR1-independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNF-α antibody alone is not sufficient.

KEYWORDS:

Cellular FLICE-inhibitory protein; TNF-α; apoptosis; epidermal differentiation

PMID:
29596938
DOI:
10.1016/j.jaci.2018.02.043

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