Elucidating the role of TNF-like weak inducer of apoptosis (TWEAK) in the pathogenesis of cutaneous lupus (BA12P.114)

Abstract

Abstract Cutaneous manifestations are very common in the systemic autoimmune disease systemic lupus erythematosus (SLE). TWEAK is a soluble cytokine member of the TNF superfamily that binds to a sole receptor, Fn14. TWEAK/Fn14 signaling is involved in cell survival, apoptosis, cytokine production, and angiogenesis, and as such has been found to be important in both tissue repair and inflammatory diseases. Whether TWEAK is involved in autoimmune skin disease is not known. We found that lupus-prone MRL/lpr mice deficient for Fn14 (Fn14KO) had attenuated cutaneous disease as compared to Fn14WT mice. MRL/lpr Fn14KO mice had significantly less epidermal acanthosis and follicular plugging, and there was decreased infiltration of T cells and macrophages as compared to Fn14WT mice. In vitro, TWEAK treatment of murine keratinocytes stimulated the secretion of RANTES (via Fn14), and promoted apoptosis. Parthenolide decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-KB. Ultraviolet light, specifically UVB, is recognized as a potent trigger of cutaneous lupus. We found that TWEAK co-treatment exacerbates UVB light- induced keratinocyte apoptosis and increases the amount of RANTES secreted, when compared to cells treated with UVB alone. These synergistic effects of TWEAK+UVB on keratinocytes were likely due to upregulation of Fn14 expression by UVB. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations of lupus.