| First Author | Piao X | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 143 |
| Issue | 1 | Pages | 213-228.e10 |
| PubMed ID | 29596938 | Mgi Jnum | J:309497 |
| Mgi Id | MGI:6757726 | Doi | 10.1016/j.jaci.2018.02.043 |
| Citation | Piao X, et al. (2019) Blockade of TNF receptor superfamily 1 (TNFR1)-dependent and TNFR1-independent cell death is crucial for normal epidermal differentiation. J Allergy Clin Immunol 143(1):213-228.e10 |
| abstractText | 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-alpha-dependent apoptosis and blocking of dermatitis. However, a role for cellular FLICE-inhibitory protein in TNF-alpha-independent cell death remains unclear. OBJECTIVE: We investigated contribution of TNF-alpha-dependent and TNF-alpha-independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar(E-KO)) mice. METHODS: We examined the histology and expression of epidermal differentiation markers and inflammatory cytokines in the skin of Cflar(E-KO);Tnfrsf1a(+/-) and Cflar(E-KO);Tnfrsf1a(-/-) mice. Mice were treated with neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand to block TNF-alpha-independent cell death of Cflar(E-KO);Tnfrsf1a(-/-) mice. RESULTS: Cflar(E-KO);Tnfrsf1a(-/-) mice were born but experienced severe dermatitis and succumbed soon after birth. Cflar(E-KO);Tnfrsf1a(+/-) mice exhibited embryonic lethality caused by massive keratinocyte apoptosis. Although keratinocytes from Cflar(E-KO);Tnfrsf1a(-/-) mice still died of apoptosis, neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand substantially prolonged survival of Cflar(E-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 Cflar(E-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-alpha antibody alone is not sufficient. |
