Psoriasis-like skin disorder in transgenic mice expressing a RIG-I Singleton-Merten syndrome variant

Mutations in DDX58 (DExD/H-box helicase 58), which encodes the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), were recently identified in the rare autoimmune disease Singleton-Merten syndrome (SMS). We report the spontaneous development of psoriasis-like skin lesions as an SMS-like symptom in transgenic mice harboring one of the RIG-I SMS variants, E373A. Histological analysis revealed typical characteristics of psoriasis, including the abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia, and infiltrates consisting of neutrophils, dendritic cells and T cells. Levels of the IL-23/IL-17 immune axis cytokines were high in the skin lesions. Rag2(-/-) transgenic mice showed partial amelioration of the phenotype, with down-regulation of inflammatory cytokines, including IL-17A, suggesting the importance of lymphocytes for the pathogenesis similar to that of human psoriasis. Of note, IL-17A deficiency abolished the skin phenotype, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved the skin manifestations even after onset. Our study provides further evidence for the involvement of RIG-I activation in the onset and progression of psoriasis via type I interferon signaling and the IL-23/IL-17 axis.

Automated summary

The study found that transgenic mice harboring certain mutations in the DDX58 gene exhibited psoriasis-like symptoms similar to Singleton-Merten syndrome, with histological analysis revealing typical psoriasis features and high levels of IL-23/IL-17 immune axis cytokines. Experiments with Rag2(-/-) transgenic mice and IL-17A deficiency revealed the importance of lymphocytes in the pathogenesis, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved skin manifestations.