Genetic Control Directed toward Spontaneous IFN-α/IFN-β Responses and Downstream IFN-γ Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease

Abstract

Psoriasis is an inflammatory skin disease, onset and severity of which are controlled by multiple genetic factors; aberrant expression of and responses to several cytokines including IFN-α/IFN-β and IFN-γ are associated with this “type 1” disease. However, it remains unclear whether genetic regulation influences these cytokine-related abnormalities. Mice deficient for IFN regulatory factor-2 (IRF-2) on the C57BL/6 background (IRF-2−/−BN mice) exhibited accelerated IFN-α/IFN-β responses leading to a psoriasis-like skin inflammation. In this study, we found that this skin phenotype disappeared in IRF-2−/− mice with the BALB/c or BALB/c × C57BL/6 F1 backgrounds. Genome-wide scan revealed two major quantitative trait loci controlled the skin disease severity. Interestingly, these loci were different from that for the defect in CD4+ dendritic cells, another IFN-α/IFN-β-dependent phenotype of the mice. Notably, IFN-γ expression as well as spontaneous IFN-α/IFN-β responses were up-regulated several fold spontaneously in the skin in IRF-2−/−BN mice but not in IRF-2−/− mice with “resistant” backgrounds. The absence of such IFN-γ up-regulation in IRF-2−/−BN mice lacking the IFN-α/IFN-β receptor or β2-microglobulin indicated that accelerated IFN-α/IFN-β signals augmented IFN-γ expression by CD8+ T cells in the skin. IFN-γ indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2−/−BN mice lacked the IFN-γ receptor. Our current study thus revealed a novel genetic mechanism that kept the skin immune system under control and prevented skin inflammation through regulating the magnitude of IFN-α/IFN-β responses and downstream IFN-γ production, independently of CD4+ dendritic cells.