Journal
KIDNEY INTERNATIONAL
Volume 97, Issue 2, Pages 289-303Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2019.09.031
Keywords
lupus; lupus nephritis; Notch-3; SLE; YB-1
Categories
Funding
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [RA 740/9-1, RA 740/8-1, RA 1927/5-1, OS 196/2-1, OS 196/4-1]
- START-Program (Faculty of Medicine, RWTH, Aachen, Germany)
- DFG [INST 948/45-1 FUGG]
- Interdisciplinary Center for Clinical Research within the Faculty of Medicine at the RWTH Aachen University, Germany (IZKF) [E7-2, E7-7]
- [SFBTRR57]
- [SFBTRR219]
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Systemic lupus erythematosus (SLE) is an autoimmune disease and lupus nephritis is a major risk factor for morbidity and mortality. Notch-3 signaling induced by membrane-bound or soluble ligands such as YB-1 constitutes an evolutionarily conserved pathway that determines major decisions in cell fate. Mass spectrometry of extracellular YB-1 in sera from patients with SLE and lupus-prone mice revealed specific post-translational guanidinylation of two lysine residues within the highly conserved cold-shock domain of YB-1 (YB-1-G). These modifications highly correlated with SLE disease activity, especially in patients with lupus nephritis and resulted in enhanced activation of Notch-3 signaling in T lymphocytes. The importance of YB-1:Notch-3 interaction in T cells was further evidenced by increased interleukin (Il)10 expression following YB-1-G stimulation and detection of both, YB-1-G and Notch-3, in kidneys of MRL.lpr mice by mass spectrometry imaging. Notch-3 expression and activation was significantly up-regulated in kidneys of 20-week-old MRL.lpr mice. Notably, lupus-prone mice with constitutional Notch-3 depletion (B6.Fas(lpr/lpr)Notch3(-/-)) exhibited an aggravated lupus phenotype with significantly increased mortality, enlarged lymphoid organs and aggravated nephritis. Additionally, these mice displayed fewer regulatory T cells and reduced amounts of antiinflammatory IL-10. Thus, our results indicate that the YB1:Notch-3 axis exerts protective effects in SLE and that Notch-3 deficiency exacerbates the SLE phenotype.
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