Epidermal IFN-κ drives cutaneous lupus-like lesions, photosensitivity and systemic autoimmunity in mice

Summary: Abstract Body: Keratinocyte-derived interferon kappa (IFN-κ) is an important mediator of photosensitive responses in cutaneous lupus erythematosus (CLE) and is chronically overexpressed in systemic lupus erythematosus (SLE) skin. Recent evidence suggests that the epidermis itself instructs the innate and adaptive immune system in SLE to contribute to disease onset and flares, but whether epidermal IFN-κ alone is sufficient to drive CLE or SLE has not been investigated. 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 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 and bulk RNA sequencing and subsequently compared to human CLE. Flow cytometry on lymph nodes and splenocytes at baseline and after UV exposure was performed to phenotype immune cell compositions. Importantly, 75% of aged TG mice exhibited CLE-like lesions with strong lymphocytic infiltration and a transcriptional signature reflective of cytokine/chemokine secretion, IFN-signaling and T-cell activation, as seen in human CLE. Strikingly, UV exposure in young TG mice resulted in a significant shift of splenic naïve CD8+ T cells (CD62L+CD44-) towards effector memory CD8+ T cells (CD62L-CD44+) in TG compared to WT mice. Furthermore, aged TG mice developed spontaneous signs of systemic autoimmunity reflected by autoantibodies against dsDNA, high total IgG and lymphopenia, but they did not exhibit detrimental organ failure. Our results indicate an axis from an IFN-rich epidermis towards systemic inflammation and provide a new murine CLE model with strong parallels to human CLE. Benjamin Klein¹, Deborah Colesa¹, Kelsey McNeely¹, Yiqing Gao¹, Patrick O'Brien¹, Thi Kim Nguyen¹, Johann E. Gudjonsson¹, Celine Berthier¹, Michelle Kahlenberg¹ 1. University of Michigan, Ann Arbor, MI, United States. Adaptive and Auto-Immunity