The role of TWEAK and Fn14 in ultraviolet light-induced cutaneous lupus

• Published in: The Journal of immunology (1950) 2016-05, Vol.196 (1_Supplement), p.48-48.7
• Main Authors: Doerner, Jessica L, Chalmers, Samantha A., Friedman, Adam, Putterman, Chaim
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.196.Supp.48.7

Cutaneous lupus erythematosus (CLE) is a common disease manifestation in SLE patients. Ultraviolet-B irradiation (UVB) is well-known trigger of CLE; many lupus patients are photosensitive, and develop skin lesions following sun exposure. TWEAK, a TNF superfamily member, is a soluble cytokine that binds a sole signaling receptor, Fn14. TWEAK/Fn14 interactions are important in key biologic processes, including angiogenesis, cell death and inflammation, and are often upregulated during tissue injury. We found that MRL-lpr/lpr (MRL/lpr) lupus-prone mice deficient for the Fn14 receptor (Fn14KO) had markedly attenuated skin lesions following UVB irradiation, as compared to Fn14WT mice. Histologically, MRL/lpr Fn14WT mice had more keratinocyte apoptosis, degeneration of the basement membrane, and dermal inflammation. Further evaluation showed decreased infiltration of IBA-1+ macrophages, CD3+ T cells, and NGAL+ cells (neutrophils) in the skin of MRL/lpr Fn14KO mice. Depletion of macrophages in MRL/lpr mice using the CSF1R/fms kinase inhibitor GW2580 attenuated irradiation-induced tissue injury, confirming a pathogenic role for these Fn14-expressing cells in UVB-induced lesions. Several key chemokines (including MCP-1, MIP-1α, MIP-1β) were decreased following macrophage depletion and also differentially expressed between Fn14KO and WT mice, suggesting regulation through TWEAK/Fn14 signaling. Finally, both in vitro and in vivo, Fn14 was upregulated on dead and dying cells following irradiation, which can locally sensitize cells to the effects of TWEAK. Our data reveals important contributors to the pathogenesis of UVB-induced cutaneous lesions, and suggests a novel role for TWEAK/Fn14 signaling in skin disease.