Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome
| Autor: | Sung-Sen Yang, Ann Chen, Ching-Liang Chu, Yu-Chuan Lin, Chung-Yao Wu, Shun-Min Yang, Feng-Cheng Liu, Shin-Ruen Yang, Shuk-Man Ka, Kuo-Feng Hua, Jack L. Arbiser |
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| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Tris Inflammasomes MAP Kinase Signaling System T cell Kidney Glomerulus Immunology Lupus nephritis Cell Communication Lymphocyte Activation Severity of Illness Index T-Lymphocytes Regulatory Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine NLR Family Pyrin Domain-Containing 3 Protein Autophagy Organometallic Compounds medicine Animals Humans Immunology and Allergy Chemistry Cell growth Glomerulonephritis Inflammasome Dendritic Cells medicine.disease Lupus Nephritis Disease Models Animal medicine.anatomical_structure Cancer research Female 030215 immunology medicine.drug |
| Zdroj: | The Journal of Immunology. 204:1448-1461 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1801610 |
| Popis: | Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow–derived dendritic cell–mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis. |
| Databáze: | OpenAIRE |
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