TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus

Jessica L. Doerner, Jing Wen, Yumin Xia, Karin Blecher Paz, David Schairer, Lan Wu, Samantha A. Chalmers, Peter Izmirly, Jennifer S. Michaelson, Linda C. Burkly, Adam J. Friedman, Chaim Putterman

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)1986-1995
Number of pages10
JournalJournal of Investigative Dermatology
Volume135
Issue number8
DOIs
StatePublished - Aug 21 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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    Doerner, J. L., Wen, J., Xia, Y., Paz, K. B., Schairer, D., Wu, L., Chalmers, S. A., Izmirly, P., Michaelson, J. S., Burkly, L. C., Friedman, A. J., & Putterman, C. (2015). TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus. Journal of Investigative Dermatology, 135(8), 1986-1995. https://doi.org/10.1038/jid.2015.124