Epidermal Interferon-κ Drives Cutaneous Lupus-Like Lesions, Photosensitivity, and Systemic Autoimmunity In Vivo

Keratinocyte-derived interferon (IFN) κ is chronically overexpressed in human nonlesional systemic lupus erythematosus (SLE) skin. Recent evidence suggests that epidermal signals instruct the immune system in SLE, but whether epidermal IFNκ alone is sufficient to drive lupus phenotypes has not been investigated. This study aimed to identify whether epidermal-specific overexpression of IFN-κ (Ifnk) results in lupus-like cutaneous and systemic inflammation.

We compared 3-month-old (young) and 12-month-old (aged) Balb/c mice who overexpress Ifnk in the epidermis under the keratin 14 promoter (transgenic [TG]) with age-matched Balb/c wild-type mice and assessed local and systemic immune responses at baseline and after UV treatment. Skin lesions were assessed by histopathology, bulk RNA sequencing, and immunohistochemistry and subsequently compared to human cutaneous lupus erythematosus (CLE). Flow cytometry on lymph nodes and splenocytes at baseline and after UV treatment was performed to phenotype immune cell compositions.

Ifnk TG mice spontaneously developed CLE-like lesions and systemic immune dysregulation. Lesions showed facial predominance, lymphocytic infiltration, immune complex deposition, and a transcriptional signature reflective of human CLE. Ifnk TG mice exhibited increased immune cell activation and spontaneous signs of systemic autoimmunity with higher anti-double-stranded DNA antibodies, lymphadenopathy, and splenomegaly but lacked signs of renal inflammation. UV treatment 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 IFNκ as a driver of CLE, photosensitivity, and systemic inflammation.