Tweaking the skin: The role of TWEAK/Fn14 in the pathogenesis of cutaneous lupus
Doemer, Jessica L.
MetadataShow full item record
Cutaneous lupus erythematosus (CLE) is a common manifestation of systemic lupus erythematosus (SLE), and for many patients is the first sign of disease. The pathogenesis of CLE is not fully understood; however, the contributions of apoptosis, immune cells, and cytokines play an important role in disease development. It is also well established that UVB irradiation can precipitate skin disease and systemic disease in patients. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSFI2) and its sole receptor Fn14 are involved in cell survival, cytokine production, inflammation, and apoptosis. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored.;We found that TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and also promoted apoptosis. When combined with TWEAK treatment in vitro, UVB irradiation led to increased RANTES production and apoptosis. MRL/Ipr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any differences in the severity of cutaneous lesions. MRL/lpr Fn14 KO mice had significantly attenuated cutaneous disease as compared with their Fn14 WT littermates. The architecture of the skin of Fn14 KO was well maintained and there was decreased infiltration of T cells and macrophages into the skin of these mice.;We also wanted to explore the role of TWEAK/Fn14 in the pathogenesis of UVB induced lesions. MRL/lpr Fn14 KO mice were compared to MRL/lpr Fn14 wild-type (WT) following exposure to UVB, again to evaluate for differences in cutaneous lesions. MRL/lpr KO mice had noticeably reduced cutaneous disease when compared to their WT counterparts. There were also fewer infiltrating immune cells (CD3+, IBA-1+ and NGAL+) in the skin of MRL/lpr Fn14 KO mice, and several pro-inflammatory chemokines were upregulated after UV, at both the RNA and protein level. Depletion of macrophages, using a CSF-1 R kinase inhibitor, was found to be protective against the development of lesions after UVB exposure.;Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus, as well as UVBinduced cutaneous lupus, and suggest a possible target for therapeutic intervention.
- Theses and Dissertations