IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation
Source:Yuping Lai
Atopic dermatitis (AD) and psoriasis are clinically independent inflammatory skin diseases. AD is strongly driven by type 2 T helper cells (TH2 cells) and is associated with interleukin-4 (IL-4) and IL-13 overproduction, while psoriasis is largely driven by TH17 cells and associated with IL-17 activation. Although an abnormal keratinocyte response to T cell-derived cytokines is intrinsic to the pathology of AD and psoriasis, whether they share common mechanisms that regulate keratinocyte inflammation remains unclear.

On October 21, 2022, the group led by Yuping Lai from East China Normal University published the manuscript entitled “IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation” in Nature Immunology. They revealed that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.

To delineate the underlying mechanism between AD and psoriasis, the authors analyzed overlapping differentially expressed genes (DEGs) from publicly available RNA-Seq dataset (GEO database: accession no. GSE121212) and single-cell RNA-seq (scRNA-Seq) datasets from healthy controls and patients with AD or psoriasis, and found that DDX5 mRNA was significantly downregulated in keratinocytes of lesional skin from AD and psoriasis compared with healthy skin. Immunofluorescence staining further confirmed that expression of DDX5 protein was reduced in epidermal keratinocytes from patients with AD and psoriasis. Moreover, both mRNA and protein levels of DDX5 were profoundly reduced in lesional skin of OVA- or MC903-induced AD mice and IMQ-induced psoriasis mice. To determine the role of keratinocyte DDX5 in skin inflammation, they generated mice with a specific ablation of Ddx5 in keratinocytes by crossing Ddx5fl/fl mice with K14Cre transgenic mice, hereafter referred to as Ddx5∆KC mice. Compared with Ddx5fl/fl littermates, 72.7% of Ddx5∆KC mice spontaneously developed AD and psoriasis phenotypes 2 weeks after birth, and Ddx5∆KC mice were also more susceptible to MC903 and IMQ treatment and developed severe AD and psoriasis.

Next, the authors further uncovered the mechanism by which DDX5 mediates inflammatory responses in keratinocytes. They found that DDX5 cooperated with SF2 to regulate IL-36R pre-mRNA splicing for sIL-36R production in keratinocytes. sIL-36R antagonized IL-36R signaling by competing with IL-36R for IL-36γ binding to and then control keratinocyte inflammation. In AD and psoriasis, IL-17D was upregulated in lesional skin and activated CD93-p38 MAPK-AKT-SMAD2/3 signaling to inhibit the expression of DDX5 in keratinocytes. The reduction in DDX5 led to increased IL-36R, but decreased sIL-36R, and restoration of sIL-36R in Ddx5∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes.

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

The work in Yuping Lai’s group is supported by National Natural Science Foundation of China and National Key Research and Development Program of China. Xinhui Ni, Yi Xu and Wang Wang are co-first authors of this manuscript. Professors Tieliu Shi from East China Normal University, Wei Li from Huashan Hospital, Fudan University, Yuling Shi from Shanghai Skin Disease Hospital, Tongji University, Lin-Fa Wang from Duke-NUS Graduate Medical School, Singapore and Chen Dong from Shanghai Jiaotong University School of Medicine-affiliated Renji Hospital are coauthors.

The research interest in Yuping Lai’s group is focused on the pathogenesis and relapse of inflammatory skin diseases. The work from her group have been published in Nature Immunology, Nature Medicine, Immunity, Nature Communications and so on. Her group has won 18 grants. Yuping Lai is currently a director of Asian Society for Psoriasis, an associated editor of Frontiers in Immunology-Inflammation, members of several societies, including Chinese Society for Investigative Dermatology, Chinese Society for Immunology.