Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e
| Autor: | Natalya Seredkina, Christopher Graham Fenton, Elin Synnøve Mortensen, Silje Fismen, Thomas Elung-Jensen, Ole Petter Rekvig, Anne-Lise Kamper, Dhivya Thiyagarajan, Søren Jacobsen |
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| Rok vydání: | 2012 |
| Předmět: |
Lupus nephritis
lcsh:Medicine Kidney Biochemistry Mice Nucleic Acids Molecular Cell Biology Gene expression Receptors Immunologic lcsh:Science Receptor Cells Cultured Principal Component Analysis Multidisciplinary Physics Toll-Like Receptors Lupus Nephritis Chromatin Cell biology Nephrology Cytokines Medicine Female Nephritis Signal Transduction Research Article VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 Immunology Biophysics VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710::Medical genetics: 714 Biology Microbiology Autoimmune Diseases Molecular Genetics Rheumatology Murine lupus medicine Animals Deoxyribonuclease I Humans Gene silencing Lectins C-Type Gene Silencing RNA Messenger Inflammation lcsh:R Immunity Membrane Proteins Proteins Computational Biology DNA medicine.disease Molecular biology Disease Models Animal Clinical Immunology lcsh:Q |
| Zdroj: | PLoS ONE, Vol 7, Iss 3, p e34080 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | This paper is part of Dhivya Thiyagarajan's doctoral thesis, available in Munin at http://hdl.handle.net/10037/5484 Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7–9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease. |
| Databáze: | OpenAIRE |
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