NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation.

Snehlata Kumari,Daniela Preukschat,Trieu-My Van,Marijana Basic,Hannah Schuenke,Ulf Klein,André Bleich,Manolis Pasparakis

doi:10.26508/lsa.202000956

Abstract

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.

Highlights

The skin constitutes an essential structural and immunological barrier protecting the organism from microbial challenges
Our genetic studies identified RIPK3MLKL-dependent keratinocyte necroptosis as a key inducer of skin inflammation in IKK2E-KO and RelAE-KO c-RelE-KO mice, consistent with the notion that necroptosis is an inflammatory type of cell death
It is notable that keratinocytes lacking IKK2 or RelA and c-Rel underwent TNF-induced necroptosis in vivo even though they had intact FADD-caspase-8 signaling. It remains unclear how inhibition of IKK/NF-κB signaling sensitizes keratinocytes to necroptosis in the presence of intact caspase-8 activity, these results suggest that regulation of necroptosis within the tissue microenvironment may be different from the in vitro cell culture systems typically used for the study of necroptosis

Summary

Introduction

The skin constitutes an essential structural and immunological barrier protecting the organism from microbial challenges. The maintenance of a healthy skin homeostasis requires a proper balance between cell proliferation, differentiation, death, and a tightly regulated cross talk between epithelial and immune cells. Deregulation of this balance results in chronic inflammatory skin diseases, such as psoriasis. Whereas early studies of the mechanisms driving the pathogenesis of inflammatory skin diseases focused on the role of immune cells, recent studies in genetic mouse models have highlighted the importance of keratinocyteintrinsic mechanisms in regulating skin immune homeostasis and inflammation (Pasparakis et al, 2014). Despite the proven clinical efficacy of anti-TNF therapy, the molecular mechanisms by which TNF triggers inflammation in these patients remain poorly understood

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Conclusion