Epidermal Interferon kappa drives cutaneous lupus-like lesions, photosensitivity and systemic autoimmunity in vivo.

Abstract

OBJECTIVE Keratinocyte-derived interferon kappa (IFN-κ) 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-κ alone is sufficient to drive lupus phenotypes has not been investigated. This study aimed to identify whether epidermal-specific overexpression of Interferon kappa (Ifnk) results in lupus-like cutaneous and systemic inflammation. METHODS We compared three month (young) and twelve month (aged) old Balb/c mice that overexpress Ifnk in the epidermis under the keratin 14 promoter (transgenic, TG) with age-matched Balb/c wild type mice (WT) and assessed local and systemic immune responses at baseline and after UV exposure. 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 exposure was performed to phenotype immune cell compositions. RESULTS Ifnk TG mice spontaneously develop CLE-like lesions and systemic immune dysregulation. Lesions show facial predominance, lymphocytic infiltration, immune complex deposition 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. CONCLUSION Together, we describe a new CLE mouse model that recapitulates features of human CLE and substantiates the role of epidermal IFN-κ as a driver of CLE, photosensitivity and systemic inflammation.