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

J Allergy Clin Immunol. 2019 Jan;143(1):213-228.e10. doi: 10.1016/j.jaci.2018.02.043. Epub 2018 Mar 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology*
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis / immunology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / immunology
  • Cell Differentiation / drug effects*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Dermatitis / genetics
  • Dermatitis / immunology*
  • Dermatitis / pathology
  • Epidermis / immunology*
  • Epidermis / pathology
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Mice
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology

Substances

  • Antibodies
  • Antigens, Differentiation
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Il17a protein, mouse
  • Interleukin-17
  • Interleukin-6
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • interleukin-6, mouse