MDA5 is an essential cytoplasmic viral RNA sensor to induce type I interferon (IFN). Previously we reported that MDA5 G821S mutant heterozygous (Ifih1gs/+) mice spontaneously develop lupus-like nephritis in an IFN dependent manner. Considering that the gain of function mutation in IFIH1 encoding human MDA5 protein has also been found in SLE patients, this Ifih1gs/+ mice has the potential to be a good tool to exploit clinical treatments for SLE patients with MDA5 mutations. However, more precise mechanisms of the pathogenesis remain to be determined.
In order to elucidate the contribution of CD11c-positive dendritic cells (DCs), we generated conditional knock-in (cKI) mice expressing MDA5 G821S mutant protein in desired tissues. Although CAG-cKI mice with ubiquitous expression of Cre by CAG promoter activity exhibited immune complexes deposition and mesangial matrix proliferation as early as 4weeks, they died before 6weeks old. Interestingly, CD11c-cKI mice survived more than half a year with lupus-like nephritis, although the onset was delayed with less severe phenotype. Further analysis in CD11c-cKI mice revealed that splenic plasmacytoid DCs produced high amounts of IFN compared with other immune cells. Flowcytometric analysis revealed that the DCs are activated as judged by elevated expression of CD86. Furthermore, expression level of CD69 as a lymphocyte activation maker was increased in splenic T and B cells. In accord with this, we observed autoantibody production in the serum.
These results demonstrate that MDA5 G821S mutation in CD11c-expressing cells is sufficient to induce lupus-like nephritis, although more moderate phenotype compared with CAG-cKI mice. Furthermore, CD11c-cKI mice are a good tool for the clinical therapy model, and DCs are potential targets of therapy for lupus patients with MDA5 mutations.