Background/Purpose: Sunlight, via ultraviolet B (UVB) irradiation, is a well-recognized trigger of cutaneous lupus erythematosus (CLE) skin lesions. TNF-like weak inducer of apoptosis (TWEAK), a TNF superfamily member (TNFRSF12), is a soluble cytokine that binds to its sole known signaling receptor, Fn14 (TNFRSF12A). TWEAK and Fn14 are upregulated following tissue inflammation and/or injury, and this signaling pathway is important in critical biologic processes including angiogenesis, cell survival, and local inflammation. Both TWEAK/Fn14 and UVB promote apoptosis and induce the production of proinflammatory cytokines; we wanted to investigate the potential synergism between these two pathways in lupus-associated skin disease by investigating the effects of UVB on lupus-prone mice with or without Fn14.

Methods: To evaluate a possible role for UVB in the pathogenesis of CLE, we exposed female lupus-prone MRL/lpr Fn14 wild type (WT) (n=14) and knockout (KO) mice (n=15) at 14-15 weeks of age to UVB irradiation (2 doses of 50 mJ/cm² each, 24 hours apart), and evaluated the severity of skin lesions 24 hours after the last dose. Histology was scored using a numerical system, and skin sections were stained and scored for infiltrating macrophages using IBA-1 immunofluorescence. Additionally, snap-frozen skin was analyzed by RT-PCR for inflammatory cytokine expression.

Results: MRL/lpr Fn14 WT mice developed significantly more severe skin involvement following exposure to UVB when compared to strain, age, and gender matched Fn14 KO mice (mean skin score: MRL/lpr Fn14 WT=3.8±0.4, MRL/lpr Fn14 KO=2.5±0.3, p-value=0.01). Histologically, MRL/lpr Fn14 WT mice had significantly more apoptotic keratinocytes and basement membrane degeneration. MRL/lpr Fn14 WT mice also had increased dermal infiltration by macrophages following UVB (MRL/lpr Fn14 WT=5.1±0.3, MRL/lpr Fn14 KO=3.3±0.3, p-value=0.0002). RT-PCR revealed higher levels of skin expression of CXCL10 (MRL/lpr Fn14 WT=5.5±1.0, MRL/lpr Fn14 KO=2.3±1.0 p-value=0.06) and RANTES (MRL/lpr Fn14 WT=6.8±1.3, MRL/lpr Fn14 KO=1.2±0.3, p-value=0.004) in MRL/lpr Fn14 WT as compared to MRL/lpr Fn14 KO mice.

Conclusion: UVB-induced skin inflammation is significantly attenuated in Fn14 deficient MRL/lpr lupus-prone mice. Our data suggests a novel role for the TWEAK/Fn14 signaling pathway in the induction of cutaneous lupus lesions following exposure to UVB irradiation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fn14-deficiency-protects-lupus-prone-mice-from-cutaneous-lesions-induced-by-ultraviolet-b-uvb-irradiation/