A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS)

Negm, Ola H.; Mannsperger, Heiko A.; McDermott, Elizabeth M.; Drewe, Elizabeth; Powell, Richard J.; Todd, Ian; Fairclough, Lucy C.; Tighe, Patrick J.

Abstract

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.

Citation

Negm, O. H., Mannsperger, H. A., McDermott, E. M., Drewe, E., Powell, R. J., Todd, I., Fairclough, L. C., & Tighe, P. J. (2014). A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS). European Journal of Immunology, 44(7), 2096-2110. https://doi.org/10.1002/eji.201344328

• Journal Article Type: Article
• Acceptance Date: Mar 21, 2014
• Online Publication Date: Jun 10, 2014
• Publication Date: 2014-07
• Deposit Date: Oct 2, 2017
• Publicly Available Date: Oct 2, 2017
• Journal: European Journal of Immunology
• Print ISSN: 0014-2980
• Electronic ISSN: 1521-4141
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 44
• Issue: 7
• Pages: 2096-2110
• DOI: https://doi.org/10.1002/eji.201344328
• Keywords: Autoinflammation; Protein microarray; Signalome; TNF receptor 1; TRAPS
• Public URL: https://nottingham-repository.worktribe.com/output/995424
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1002/eji.201344328/abstract
• Contract Date: Oct 2, 2017