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

Area of Science:

• Immunology
• Dermatology
• Rheumatology

Background:

• Keratinocyte-derived interferon kappa (IFN-κ) is overexpressed in non-lesional skin of systemic lupus erythematosus (SLE) patients.
• Epidermal signals are implicated in instructing the immune system in SLE.
• The sufficiency of epidermal IFN-κ alone in driving lupus phenotypes remains uninvestigated.

Purpose of the Study:

• To determine if epidermal-specific overexpression of Interferon kappa (Ifnk) induces lupus-like cutaneous and systemic inflammation.
• To establish a novel mouse model for studying cutaneous lupus erythematosus (CLE) pathogenesis.

Main Methods:

• Comparison of age-matched wild type (WT) and keratin 14 promoter-driven Ifnk transgenic (TG) Balb/c mice (3 and 12 months old).
• Assessment of local and systemic immune responses at baseline and post-UV exposure.
• Histopathology, RNA sequencing, immunohistochemistry, and flow cytometry were employed to analyze skin lesions and immune cell composition.

Main Results:

• Ifnk TG mice spontaneously developed CLE-like lesions with facial predominance, lymphocytic infiltration, and immune complex deposition.
• TG mice exhibited systemic immune dysregulation, including increased anti-dsDNA antibodies, lymphadenopathy, and splenomegaly, but no renal inflammation.
• UV exposure exacerbated cutaneous inflammation and splenic T cell activation in Ifnk TG mice, mirroring photosensitivity.

Conclusions:

• Epidermal-specific Ifnk overexpression is sufficient to drive CLE-like skin lesions and systemic inflammation.
• The developed mouse model recapitulates key features of human CLE, validating the role of epidermal IFN-κ.
• This model supports IFN-κ as a driver of CLE, photosensitivity, and systemic autoimmunity in lupus.