008 Smad7 dampened IL22 signaling-induced inflammation through IL22RA2 upregulation

IL22 signaling plays a critical role in the pathogenesis of skin inflammatory diseases such as psoriasis and atopic dermatitis. Smad7 is transforming growth factor β (TGFβ) inhibitor consisting an N-terminal domain, C-terminal linker region harboring PY motif. transgene expression Keratin 5 (K5)+ keratinocytes attenuated K5.TGFβ1 transgene-induced psoriatic inflammation. The downstream mechanistic players functional domains that mediates its anti-inflammatory properties whether function applies to other conditions remain be determined. Here, we showed mice expressing K5.Smad7, but not domain Smad7, caused resistance imiquimod (IMQ)-induced dermatitis compared their wildtype littermates. Further, generated truncated protein with motif (PYC-Smad7) fused cell-penetrating Tat peptide (Tat-PYC-Smad7). Topical application Tat-PYC-Smad7 significantly IMQ-induced inflammation, 2,4-dinitrofluorobenzene-induced dermatitis, tape-stripping-induced RNA sequencing analysis spatial phenotyping multiplex immunofluorescence identified only mitigated TGFβ NFκβ alleviated inflammation-induced epidermal hyperproliferation, neutrophil, macrophage T-cell infiltration, angiogenesis, STAT3 activation. These effects were mediated by upregulation IL22RA2, negative regulator IL22/STAT3 signaling. Upregulation IL22RA2 was dependent upon transcriptional C/EBP-β, which binds promotor cells PYC-Smad7. Thus, PYC-Smad7 contains dampen multiple IL-22-dependent pro-inflammatory pathways Smad7-based potential therapeutic agent for treating diseases.