IL22RA2 is a Smad7 target mediating alleviation of dermatitis and psoriatic phenotypes in mice
Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study sought to identify novel mechanisms and developmental therapeutics for these diseases using genetic models and pharmacological approaches. We found mice overexpressing Smad7 in keratinocytes, but not mice overexpressing the N-terminal domain of Smad7 (N-Smad7), were resistant to imiquimod (IMQ)-induced Th1/17 and Th2 type inflammation. We generated a truncated Smad7 protein encompassing C-terminal Smad7 and PY motif fused with cell-penetrating Tat peptide (Tat-PYC-Smad7). Topically applied Tat-PYC-Smad7 to inflamed skin entered cells upon contact and attenuated IMQ-, 2,4-dinitrofluorobenzene-induced atopic dermatitis (AD) and tape-stripping inflammation (TS). RNAseq analyses of mouse skin exposed to these insults identified that in addition to inhibiting TGFß/NF?B, Smad7 blunted IL22/STAT3 activation and associated pathogenesis, which is due to Smad7 transcriptionally upregulating IL22 antagonist IL22RA2. Mechanistically, Smad7 facilitated nuclear translocation and DNA binding of C/EBPß to IL22RA2 promoter for IL22RA2 transactivation. Consistent to the above observations in mice, transcript levels of IL22RA2 were increased in human atopic dermatitis and psoriasis lesions with clinical remission. Our study identified the anti-inflammation functional domain of Smad7 and suggests mechanism and feasibility for developing Smad7-based biologics as a topical therapy for skin inflammatory disorders. Overall design: Comparative gene expression profiling analysis using data obtained from RNA-seq data for K5.Smad7 transgenic and wildtype dorsal IMQ skin on day 6, and Tat-PYC-Smad7 and vehicle-treated  IMQ, AD and TS dorsal skin on day 6.