IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice

Abstract Pityriasis rubra pilaris (PRP) is a rare inflammatory keratinization disorder with perifollicular erythema, and most autosomal dominant familial cases of atypical juvenile (type V) PRP are caused by gain-of-function mutations in CARD14, which encodes caspase recruitment domain-containing protein 14 (CARD14). We report the first mouse model of PRP to carry a homozygous knock-in mutation, c.380G>C (p.Cys127Ser) corresponding to a PRP-causative human mutation, in CARD14. The Card14C127S/C127S knock-in mice recapitulate key aspects of human PRP, including hair follicle dilatation, follicular plugs, and palmoplantar hyperkeratosis, and show skin barrier dysfunction, the hyperactivation of innate immunity via the IL-36 signaling and inflammasome pathways, and the excessive activation of the IL-17 axis in the outer root sheath and interfollicular epidermis. Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice. Thus, this knock-in mouse is a valid model for further evaluating early events in the PRP pathogenesis and for developing PRP therapies.