IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation.

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 (Ddx5∆KC) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.

Keratinocyte: A trigger or an executor of psoriasis?

Psoriasis is a common chronic inflammatory skin disease characterized by abnormal proliferation/differentiation of keratinocytes and excessive immune cell infiltration in the dermis and epidermis. Over the past 2 decades, immune cells have been considered as the main driver of psoriasis because the neutralizing antibodies targeting the IL-23/IL-17 axis that regulates cross-talk between dendritic cells and T cells achieve tremendous success in the treatment of psoriasis. However, whether keratinocyte would be a driver of psoriasis or just an executor in response to immune cells is still under debate. In this review, we focus on the recent advances in the identification of keratinocyte as a trigger of psoriasis, summarize on the role of keratinocytes in self-perpetuating loop to maintain inflammation in psoriasis, and then discuss the possible roles of keratinocytes in the relapse of psoriasis.