In conclusion, we described the critical role of IL-22BP in mediating autoregulation of IL-22 signaling in keratinocytes to control cutaneous pathogenesis, and therefore fine tuning of the balance in the IL-22–IL-22R1–IL-22BP axis is essential to maintain epithelial homeostasis to evoke antimicrobial immunity, tissue repair at barrier surfaces, and prevent undesirable skin inflammatory disorders. This evidence concerns the gene IL22RA2 and inflammatory skin disease.