The YB-1:Notch-3 axis modulates immune cell responses and organ damage in systemic lupus erythematosus
| Autor: | Daniel M. Breitkopf, Klaus Tenbrock, Jürgen Floege, Juliane Hermann, Vera Jankowski, Xiyang Liu, Ute Raffetseder, Ina V. Martin, Elisabeth F. Gröne, Fabian Groll, Jialin Wang, Daniela Hermert, Kim Ohl, Thomas Rauen, Tammo Ostendorf |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mice Inbred MRL lpr 030232 urology & nephrology Lupus nephritis T-Lymphocytes Regulatory 03 medical and health sciences Mice 0302 clinical medicine Immune system Notch 3 immune system diseases medicine Animals Humans Lupus Erythematosus Systemic skin and connective tissue diseases Receptor Notch3 Autoimmune disease Systemic lupus erythematosus business.industry Interleukin medicine.disease Lupus Nephritis 030104 developmental biology Lymphatic system Nephrology Immunology business Nephritis Signal Transduction Transcription Factors |
| Zdroj: | Kidney international. 97(2) |
| ISSN: | 1523-1755 |
| Popis: | 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.Faslpr/lprNotch3−/−) 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 anti-inflammatory IL-10. Thus, our results indicate that the YB-1:Notch-3 axis exerts protective effects in SLE and that Notch-3 deficiency exacerbates the SLE phenotype. |
| Databáze: | OpenAIRE |
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