Blockade of TNFR1-dependent and -independent cell death is crucial for normal epidermal differentiation

Publication date: Available online 27 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Xuehua Piao, Ryosuke Miura, Sanae Miyake, Sachiko Komazawa-Sakon, Masato Koike, Ryodai Shindo, Junji Takeda, Akito Hasegawa, Riichiro Abe, Chiharu Nishiyama, Tetsuo Mikami, Hideo Yagita, Yasuo Uchiyama, Hiroyasu Nakano
BackgroundDelicate balance between cell death and proliferation of keratinocytes is crucial for normal development of the skin. Previous studies have reported that cellular FLICE-inhibitory protein (cFLIP) plays a crucial role in prevention of keratinocytes from TNFα-dependent apoptosis and blocking the development of dermatitis. However, a role for cFLIP in TNFα-independent cell death remains unclear.ObjectiveWe investigated contribution of TNFα-dependent and -independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar^E-KO) mice.MethodsWe examined histology, and expression of epidermal differentiation markers and inflammatory cytokines of the skin of Cflar^E-KO ;Tnfrsf1a+/- and Cflar^E-KO ;Tnfrsf1a-/- mice. To block TNFα-independent cell death of Cflar^E-KO;Tnfrsf1a-/- mice, mice were treated with neutralizing antibodies against FasL and TRAIL.ResultsCflar^E-KO;Tnfrsf1a-/- mice were born, but developed severe dermatitis and succumbed soon after birth. Cflar^E-KO;Tnfrsf1a+/- mice exhibited embryonic lethality due to massive apoptosis of keratinocytes. While keratinocytes from Cflar^E-KO;Tnfrsf1a-/- mice still died by apoptosis, neutralizing antibodies against FasL and TRAIL substantially prolonged survival of Cflar^E-KO;Tnfrsf1a-/- mice. Expression of inflammatory cytokines, such as interleukin (Il)6 and Il17a was elevated, 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.ConclusionTNFR1-dependent or -independent apoptosis of keratinocytes promotes inflammatory cytokine production that subsequently blocks epidermal differentiation. Thus, blockade of both TNFR1-dependent and -independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNFα antibody alone is not sufficient.

Teaser

Epidermis-specific deletion of Cflar gene uncovers that prevention of both TNFR1-dependent and -independent apoptosis is crucial for the maintenance of normal epidermal differentiation.


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