Epidermal IFN-? drives cutaneous lupus and systemic immune activation
Keratinocyte-derived interferon kappa (IFN-?) is chronically overexpressed in human non-lesional systemic lupus erythematosus (SLE) skin. Recent evidence suggests that epidermal signals instruct the immune system in SLE, but whether epidermal IFN-? alone is sufficient to drive lupus phenotypes has not been investigated. Here, we show that mice that overexpress Ifnk in the epidermis under the keratin 14 promoter (Ifnk transgenic, TG) on a BALB/c background spontaneously develop cutaneous lupus erythematosus (CLE)-like lesions and systemic immune dysregulation. Lesions show facial predominance, lymphocytic infiltration, and a transcriptional signature reflective of human CLE. Ifnk TG mice exhibit increased immune cell activation and spontaneous signs of systemic autoimmunity with higher anti-dsDNA-antibodies, lymphadenopathy and splenomegaly, but lack signs of renal inflammation. UV exposure enhanced cutaneous inflammation and splenic T cell activation in Ifnk TG mice. Together, we describe a new CLE mouse model that recapitulates features of human CLE and substantiates the role of epidermal IFN-? as a driver of CLE, photosensitivity and systemic inflammation. Overall design: Mice: 11595: Ifnk TG and BALB/c WT female and male mice at 12 months were assessed for development of skin lesions. Skin lesions were harvested and stored in RNA later prior to lysis. 11567: To phenotype UV-irradiation-driven immune responses, mice were irradiated for 2 weeks, observed for another two weeks. Inguinal lymph nodes were harvested after the observation period for RNA-bulk sequencing to characterize immune phenotypes in local lymph nodes.