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

Abstract

Mutations in DDX58, which encodes the cytoplasmic RNA sensor 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 downregulation 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.

Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders

“…Specifically, Janus kinase (JAK) inhibitors such as baracitinib hold significant promise in reducing the neurological features of Aicardi–Goutieres, though randomized-controlled trials are needed to substantiate these effects [ 160 ]. While these therapies have not been systematically attempted for SGMRT, there is evidence from animal models that they may be also effective for this condition [ 161 ]. It is unclear whether these immunomodulatory therapies can be useful for the management of glaucoma associated with these conditions and that remains a topic of investigation.…”

Immunogenetics of the Ocular Anterior Segment: Lessons from Inherited Disorders

“…In contrast, RIG-I overexpression in the respiratory system shows protection against influenza infection [ 45 ]. Transgenic mice carrying a bacterial artificial chromosome introducing the human DDX58 p.Glu373Ala variant showed psoriasis-like skin lesions with IL-23/IL-17 immune axis activation and systemic inflammation [ 46 ]. Ocular features of gain or loss-of-function DDX58 mouse strains have not been examined to date.…”